Stable, highly pure L-cysteine compositions for injection and methods of use

ABSTRACT

The subject matter described herein is directed to stable L-cysteine compositions for injection, comprising: L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in an amount from about 10 mg/mL to about 100 mg/mL; Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb; cystine in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; pyruvic acid in an amount from about 0.01 wt % to about 2 wt % relative to L-cysteine; a pharmaceutically acceptable carrier, comprising water; headspace O 2  that is less than 1.0%; dissolved oxygen present in the carrier in an amount from about 0.01 parts per million (ppm) to about 1 ppm, wherein the composition is enclosed in a single-use container having a volume of from 10 mL to 100 mL. Also described are compositions for a total parenteral nutrition regimen and methods for their use.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.16/248,460, filed Jan. 15, 2019, which is incorporated herein in itsentirety by reference.

TECHNICAL FIELD

The subject matter described herein relates generally to compositionsfor parenteral administration comprising L-cysteine that are stable andhave desirable safety attributes for extended periods of time.

BACKGROUND

L-cysteine is a sulfur-containing amino acid that can be synthesized denovo from methionine and serine in adult humans. L-cysteine performs avariety of metabolic functions. For example, L-cysteine is involved ingrowth and protein synthesis and it is a precursor for glutathione, animportant intracellular antioxidant.

L-cysteine is generally classified as a non-essential amino acid or“semi-essential” amino acid because it can be synthesized in smallamounts by the human body. However, some adults can still benefit fromL-cysteine supplementation. Further, L-cysteine has been classified asconditionally essential in some cases. For example, L-cysteine can beconditionally essential in preterm infants due to biochemical immaturityof the enzyme cystathionase that is involved in L-cysteine synthesis.Thus, there are a number of circumstances in which L-cysteinesupplementation can be desirable.

The subject matter described herein addresses the shortcomings of theart by providing L-cysteine compositions that facilitate the desiredsupplementation but with an exceptional safety, purity and stabilityprofile.

BRIEF SUMMARY

In certain aspects, the subject matter described herein is directed to asafe, stable L-cysteine composition for parenteral administration,comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof in an amount from about 10 mg/mL to about 100 mg/mL;

Aluminum (Al) in an amount from about 1.0 part per billion (ppb) toabout 250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

a pharmaceutically acceptable carrier, comprising water;

headspace O₂ that is from about 0.5% to 4.0% from the time ofmanufacture to about 1 month from manufacture when stored at roomtemperature;

dissolved oxygen present in the carrier in an amount from about 0.1parts per million (ppm) to about 5 ppm from the time of manufacture toabout 1 month from manufacture when stored at room temperature,

wherein the composition is enclosed in a single-use container having avolume of from about 10 mL to about 100 mL.

In certain aspects, the subject matter described herein is directed to asafe, stable L-cysteine composition for parenteral administration,comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof in an amount from about 10 mg/mL to about 100 mg/mL;

Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) toabout 250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

a pharmaceutically acceptable carrier, comprising water;

headspace O₂ that is from about 0.5% to 4.0% from the time ofmanufacture to about 1 month from manufacture when stored at roomtemperature;

dissolved oxygen present in the carrier in an amount from about 0.1parts per million (ppm) to about 5 ppm from the time of manufacture toabout 1 month from manufacture when stored at room temperature,

optionally one or more metals selected from the group consisting of Leadfrom about 1.0 ppb to about 10 ppb, Nickel from about 5 ppb to about 40ppb, Arsenic from about 0.1 ppb to 10 ppb, and Mercury from about 0.2ppb to about 5.0 ppb;

wherein the composition is enclosed in a single-use container having avolume of from about 10 mL to about 100 mL.

In certain aspects, the subject matter described herein is directed to asafe, stable composition from about 100 mL to about 1000 mL foradministration via a parenteral infusion within about 24 to about 48hours of admixture, comprising a mixture of a composition of L-Cysteinedescribed herein; and an amino acid composition that is essentially freeof L-Cysteine comprising one or more amino acids selected from the groupconsisting of: leucine, isoleucine, lysine, valine, phenylalanine,histidine, threonine, methionine, tryptophan, alanine, arginine,glycine, proline, serine, and tyrosine.

In certain aspects, the subject matter described herein is directed to amethod of reducing Aluminum administration from a total parenteralnutrition regimen comprising L-cysteine, the method comprising, mixing acomposition comprising L-cysteine or a pharmaceutically acceptable saltthereof and/or hydrate thereof comprising:

Aluminum in an amount from about 1.0 parts per billion (ppb) to about250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine; and

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

with a composition comprising one or more amino acids selected from thegroup consisting of: leucine, isoleucine, lysine, valine, phenylalanine,histidine, threonine, methionine, tryptophan, alanine, arginine,glycine, proline, serine, and tyrosine; and

a pharmaceutically acceptable carrier, comprising water, to form acomposition for infusion having a volume of about 100 mL to about 1000mL, wherein the Aluminum provided in said parenteral nutrition regimenis from about 1-2 to about 4-5 micrograms/kg/day.

In certain aspects, the subject matter described herein is directed tomethods of treating a subject having an adverse health condition that isresponsive to L-cysteine administration, comprising:

diluting a stable L-cysteine composition as described herein with anintravenous fluid to prepare a diluted L-cysteine composition forinfusion; and

infusing the diluted L-cysteine composition for infusion to a subject toprovide a therapeutically effective dose of L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof to thesubject in a therapeutically effective dosing regimen.

In certain aspects, the subject matter described herein are directed tomethods of administering L-Cysteine together with a composition forparenteral nutrition, comprising:

diluting a stable L-cysteine composition for injection as describedherein with a parenteral nutrition composition to form a mixture; and

parenterally administering the mixture to a subject in need thereof in atherapeutically and/or nutritionally effective dose. In one aspect, thesubject is a preterm infant or newborn to about 1 month of age. Some ofthese subjects may weigh from about 0.5 kilos to about 2.0 kilos. Inanother aspect, the subject is a pediatric patient that is of about 1month to six months of age. Some of these subjects may weigh from about0.2 kilos to about 20 kilos. In another aspect, the subject is an adultrequiring parenteral nutrition.

These and other aspects are more fully described herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the overall trend of the results from the experimentsthat demonstrate the effectiveness of the Head Space Reduction (HSR)cycle in attaining reduced and consistent dissolved oxygen (DO) levelsin the finished drug product. The results showed a trend with anincrease in dissolved oxygen level from 0.36 parts per million (ppm)recorded during compounding, to an average of 5.12 ppm measured afterfilling, a further increase to an average of 9.92 ppm while loading theLyophilizer, and finally a reduction of dissolved oxygen to an averageof 0.50 ppm after headspace reduction. This demonstrates the specificphase of manufacturing at which and to the specific level that oxygenneeds to be controlled in the product.

FIG. 2 depicts the overall trend of the results from the experimentsthat demonstrate the effectiveness of the Head Space Reduction (HSR)cycle in attaining reduced and consistent dissolved oxygen (DO) levelsin the finished drug product. The results showed a trend with anincrease in dissolved oxygen level from 0.36 parts per million (ppm)recorded during compounding, to an average of 5.12 ppm measured afterfilling, a further increase to an average of 9.92 ppm while loading theLyophilizer, and finally a reduction of dissolved oxygen to an averageof 0.50 ppm after headspace reduction.

FIG. 3 depicts a process filler set up to fill and reduce head spaceoxygen.

FIG. 4 shows data for the process of Example 4. The plot showscomparison of oxygen headspace control between the lyophilizer chamberheadspace control method versus the high-speed filler vacuum stopperingsystem. The time zero oxygen headspace results for the batch PROT-000213are shown in comparison to the previously manufactured lots. Resultsshown were measured at the time of manufacturing on samples of vialsfrom the batches.

FIG. 5 depicts the data measured for dissolved oxygen levels in theprocess of Example 4.

DETAILED DESCRIPTION

The presently disclosed subject matter will now be described more fullyhereinafter. However, many modifications and other embodiments of thepresently disclosed subject matter set forth herein will come to mind toone skilled in the art to which the presently disclosed subject matterpertains having the benefit of the teachings presented in the foregoingdescriptions. Therefore, it is to be understood that the presentlydisclosed subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims. Inother words, the subject matter described herein covers allalternatives, modifications, and equivalents that are within theordinary skill in the art. In the event that one or more of theincorporated literature, patents, and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols. Unless otherwise defined, all technical and scientific termsused herein are intended to have the same meaning as commonly understoodby one of ordinary skill in this field. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety.

Advantageously, it has been found that the desirable attributes ofL-cysteine compositions for infusion can be obtained without thecharacteristic impurity profile that is known in the art. Such impurityprofile makes the product less safe to be used by patients, inparticular, preterm and term infants and pediatric patients of 1 monthto 1 year as well as critically ill adults. Specifically, the artformulations fail to address the issues related to the amounts ofAluminum and cystine, among other impurities, that can be routinelypresent and co-administered with L-cysteine. It has now been found thatL-cysteine compositions for injection can be prepared using the methodsdescribed herein whereby the compositions unexpectedly compriseexceedingly low levels of Aluminum and other undesirable impurities,such as cystine, pyruvic acid, certain heavy metals and certain ions. Asa result, the present compositions and methods of using saidcompositions are safer to the intended subject compared to the currentlyavailable compositions and methods. Further, the product is alsorendered more stable by virtue of lower levels of cystine generated bythe manufacturing processes described herein.

As described herein, without being bound to theory, it has been foundthat the problems of safety, purity and stability are results not simplyor directly from the level of Aluminum, but are also intertwined withdissolved oxygen levels in the composition and oxygen in the headspaceas well as certain heavy metals and certain ions that may leach or beextracted out of the container closure.

An L-Cysteine for injection product was prepared with the aim to providea product that would be acceptable for administration to infants,pediatric and adult patients. High quality Schott glass vials andstoppers were used. See Example 2. It was however found that glasscontainers contribute more significantly than expected to the Aluminumcontent of L-cysteine compositions stored therein to the point where theproduct did not meet the specifications for certain components. Productshaving such Aluminum levels would likely be deemed unsafe by the FDA. Assuch, efforts were focused on identifying the sources of Aluminum in theproduct and attempts to minimize it in the product. These efforts led tothe unexpected discovery that simply removing a source of Aluminum byreplacing glass with plastic did not result in a product having thedesired properties.

Additional efforts to identify the root cause for the product failureled to the finding that the product likely failed because oxygen enteredthe plastic container and into the product at a rate higher thanpreviously expected or predicted. For example, the plastic containerproduct failed in some cases in less than 1-2 months. See Example 3.This finding was also unexpected. Increased oxygen levels in the productled to unacceptable levels of oxidation products, such as cystine, whichprecipitated and caused particulates in the product. Particulates aredangerous in injectable compositions and create a safety concern, inaddition to the stability issue to the product.

However, the precipitation may have been exacerbated by reduction inAluminum since Aluminum in solution may have a stabilizing effect.Consequently, removing Aluminum may have the unintended consequence ofincreased precipitation and product failure in the presence of evensmall amounts of oxygen in the container. This was unexpected.

Additionally, controlling heat in the process including during thecompounding and/or sterilization activities, unexpectedly was found tobe beneficial for preparing stable L-Cysteine compositions describedherein. This was surprising because L-Cysteine has been used inparenteral products as an excipient where the product is subjected toterminal sterilization which exposes the product to high temperaturessuch as 120° C.

Some subjects that would be receiving L-Cysteine supplementation are, asdiscussed elsewhere herein, pre-term neonates or full-term infants thatare underweight, or infants that may be full term and are notunderweight but are still candidates for treatment, in many cases forlonger term treatment. For example, some of these subjects may betreated with L-Cysteine for several days or several weeks, even severalmonths. In these cases, it is imperative that the subjects are notexposed to potentially toxic or undesirable levels of some anions andheavy metals that may be present in drug products. Examples of suchheavy metals include but not limited to Lead, Nickel, Arsenic andMercury. Examples of anions that should be monitored include but notlimited to iodide, and fluoride. Many of these are introduced into drugproducts through manufacturing processes, container closure systems, orthe drug substance and the excipients. The levels of the heavy metalsand anions may not be a concern with many drug products because thepatient population exposed to the drug may be not as vulnerable as inthe case of L-Cysteine, or the dosing of such drug products may be verylimited, i.e., for one or a few doses. For the reasons noted above, itis imperative that L-Cysteine drug product, its administration, itsmanufacture, and its container closure system are carefully evaluatedfor the levels of heavy metals and selected anions. The state of the artis lacking in providing any specific guidance on the need for thisevaluation, the specific heavy metals and anions on which to focus, andhow to achieve control over the levels. The L-Cysteine compositions,methods of administration and manufacture, selection of containerclosure system and the excipients and the drug substance as describedherein fill that need.

Thus, in summary, as described herein, reducing aluminum drastically toextremely low levels in the product, reducing oxygen to very low levelsin the process and in the composition, and/or reducing or eliminatingheat in the process, and in consideration of data showing selection ofthe appropriate container, stopper, drug substance, and excipients,individually or in combination(s), resulted in achieving a safe, stablecomposition of L-Cysteine injection that could be administered safelyeven to very delicate pediatric subjects such as pre-term neonatalsubjects that are as young as a day and may weigh as low as 0.5 kilos,for a few days to several weeks.

L-cysteine for injection is a marketed product used as a component of anutritional supplement regimen referred to as total parenteral nutrition(TPN). The Aluminum content in known L-cysteine compositions forinjection is higher than desired. Moreover, when the L-cysteinecomposition is combined with certain amino acids prior toadministration, the amino acids contribute some amount of Aluminum, andAluminum levels can further increase. TPN admixtures constitute severalother components (in addition to amino acid mixtures) such aselectrolytes (such as Potassium Phosphate, Calcium gluconate, and sodiumacetate). These electrolytes may also contribute to high Aluminum levelsin TPN admixtures (Smith et al., Am. J. Health Syst. Pharm., vol. 64,Apr. 1, 2007, pp. 730-739). This is of particular concern sinceadministration of the L-cysteine is often to infants (some of thempre-term) for nutritional support. A focus of the subject matterdescribed herein is in minimizing the Aluminum levels coming fromL-Cysteine compositions so that when admixed with other ingredients ofTPN admixtures, the overall Aluminum levels could be reduced whileminimizing introduction of undesirable materials such as heavy metals,anions, and particulates. All of these components are present in amountsthat are below levels determined to be safe.

L-cysteine (2-Amino-3-sulfhydrylpropanoic acid) is a sulfur-containingamino acid having a structure according to Formula I:

L-cysteine performs a variety of metabolic functions. For example,L-cysteine is a precursor for antioxidants, such as glutathione andtaurine, that support oxidative defense and a healthy immune system.L-cysteine can also play a role in the synthesis of essential fattyacids and facilitate production of cell membranes and protective coversof nerve endings. Additionally, L-cysteine can be an important precursorfor many proteins, such as structural proteins in connective tissue.Thus, the depletion or absence of cystathionase activity in prematurefetuses and newborns to synthesize L-cysteine de novo has led to thecategorization of L-cysteine as a conditionally essential amino acid.Additionally, administration of L-cysteine can be valuable to treat anumber of conditions in subjects, whether or not the subject is apremature infant or neonate.

Known pharmaceutical compositions that contain L-cysteine can typicallycontain undesirable levels of certain components. Cystine is anoxidation product of L-cysteine. Like L-cysteine, cystine can besynthesized in the liver. Further, both L-cysteine and cystine can bepresent as amino acid residues in proteins. However, because cystine isan oxidation product of L-cysteine, it is possible that the amount ofcystine can increase over time. Thus, it may be desirable to maintainthe amount of cystine within predetermined levels over time. For allpractical purposes, cystine and L-Cystine are used interchangeablyherein. Pyruvic acid is another undesirable compound that can be foundin L-cysteine compositions known in the art. It is possible that theamount of pyruvic acid in these compositions can increase over time.Thus, it may be desirable to maintain the amount of pyruvic acid withinpredetermined levels over time.

Perhaps of most concern is the level of Aluminum in known L-cysteinecompositions. Aluminum contamination and associated Aluminum toxicitycan lead to a number of adverse conditions such as metabolic bonedisease, neurodevelopmental delay, cholestasis, osteoporosis, growthfailure, dementia, and the like. It is desirable to allow no more than4-5 mcg/kg/day of Aluminum to avoid toxicity. It is preferable to keepthe dose on the conservative side as much as possible, i.e., at 4mcg/kg/day to avoid accidental overdosing in case Aluminum from someother reason (unanticipated or unknown source or due to human error) isintroduced. Up to now, known L-cysteine compositions contain up to 5000ppb Aluminum. Even levels of 900 ppb are known in currently availableproducts. In stark contrast, described herein are compositions thatprovide a therapeutically effective amount of L-cysteine, whilecontaining less than 250 ppb Aluminum, including, in certainembodiments, less than 200 ppb, or less than 175 ppb, or less than 150ppb, or less than 125 ppb, or less than 120 ppb, or less than 100 ppb,or less than 80 ppb, or less than 75 ppb, or less than 60 ppb, or lessthan 50 ppb, or less than 40 ppb, or less than 30 ppb, or less than 20ppb, or less than 10 ppb, or less than 5 ppb, or less than 1.0 ppb.Thus, what has now been achieved is an unexpected and substantialreduction in Aluminum content of an L-Cysteine composition that permitsexposure to less than or equal to 4-5 micrograms per kilogram per day(μg/kg/d) to avoid or minimize Aluminum toxicity while still providingtherapeutically effective L-cysteine in a stable composition. In someaspects, the compositions described herein permit an Aluminum dose of aslow as 0.6 micrograms/kg/d, improving significantly the safety of theL-Cysteine product and its administration.

High risk patient populations for Aluminum toxicity in the context ofparenteral nutrition include the following: Renal Insufficiency andInfants: Renal elimination is a major source of Aluminum removal.Therefore, patients with renal compromise and infants with immaturerenal function are at risk of Aluminum accumulation. Pregnant women: Thefetus is vulnerable to Aluminum contamination in parenteral nutritionsince Aluminum may be transferred across the placenta. Elderly: Age is awell-known risk factor for renal impairment and thus results in a higherrisk of Aluminum toxicity. Other studies suggest that Aluminum toxicitymay be due to increased absorption of Aluminum due to a weakened GIprotective barrier.

The compositions and methods described herein provide the means tosupport the nutritional needs of patients, including preterm infants orinfants with low birth weight, but reduce the risks associated withAluminum ingestion. Most preterm and low birth weight infants tend torequire parenteral nutrition with amino acid supplementation duringtheir hospital stay. However, as mentioned above, infants are aparticularly high-risk population for Aluminum toxicity. To address suchissues, in certain embodiments, the compositions comprise about 34.5mg/mL of L-cysteine (measured as a base, i.e., not measured as HCl andmonohydrate) and no more than 250 ppb, preferably about 120 ppb, orlower, of Aluminum. These compositions with no more than 120 ppb ofAluminum, and in certain embodiments, about 120 ppb, or 100 ppb, or 80ppb, or 60 ppb, or 50 ppb, or 20 ppb, or 10 ppb or 5 ppb or 1.0 ppb, orany suitable subrange encompassing the specific values, in units of 5ppb, permit great flexibility with respect to the amino acidsupplementation for TPN preparations.

L-Cysteine injection is administered after being added to a parenteralnutrition composition such as an amino acid composition, or asugar-source such as dextrose or a lipid source or a combination of theforegoing. It is preferred that L-Cysteine is added to the amino acidcomposition, which may be administered separately or in combination withother components of a parenteral nutrition regime such as sugars andlipids. For present purposes, the Aluminum content of the combinedL-Cysteine and amino acid solution is of interest, and is monitored.L-Cysteine may be dosed at 15 mg per gram of amino acids or sometimes ata high concentration, i.e., 40 mg/gram of amino acids.

Commercially available amino acid product labeling for example indicatesthat 25 mcg/L of Aluminum is contributed from the product itself. Thegeneral recommended maximum dose is 4 g of amino acids/kg body weight.Generally amino acids solutions are available as 10% (10 g/100 mL) whichwould necessitate 40 mL volume to be administered for a 1 kg pretermneonatal patient. Based on this the amino acids solution is expected tocontribute to about 1 mcg/kg/day. This leaves about 3 mcg/kg/day fromother sources including L-cysteine. In some scenarios, there may be fiveor more other components including L-cysteine that can contribute tovarying levels of Aluminum in TPN mixtures. For the sake ofillustration, assume there are five contributors that contributeequally. The expected maximum Aluminum contribution that may come fromL-Cysteine would be (3 mcg/kg/day)/5=0.6 mcg/kg/day. In light of Smithet al. (Am. J. Health Syst. Pharm., vol. 64, Apr. 1, 2007, pp. 730-739),significant contributors to Aluminum levels besides amino acids andL-Cysteine are Potassium Phosphate, Potassium Acetate, Sodium Acetate,and Calcium Gluconate. The reference indicates that contributions fromall of these are high such that 100% of pediatric (including preterm andfull-term infants) TPNs have >4 μg/kg/day (range 12-162 μg/kg/day) ofAluminum coming from various sources. Even after carefully selecting theproducts with the least Aluminum content components among thoseavailable for treatment, the TPNs have >4 μg/kg/day. This finding forexample highlights the need to systematically reduce the amount ofAluminum in each product that will be incorporated into a TPN admixture.The current efforts are directed to providing L-Cysteine compositionsthat offer exceedingly low Aluminum levels.

One of the difficulties with establishing dosing levels of L-Cysteinewith an eye to keep the Aluminum administration to below or at a certainamount is the lack of uniformity in the art as to how to categorize thesubjects in terms of their age and weight. This imprecise terminologyhas been used often blurring the boundaries among the patient groups,making it difficult to assess which patient should receive what amountof L-Cysteine, and hence how much Aluminum would result. As such, theart does not suggest what the levels of Aluminum exposure should be, nordoes it provide a solution that minimizes Aluminum exposure during a TPNregimen. Following Table 1 shows a streamlined approach to categorizethe potential patient population and their proposed daily doses ofL-Cysteine.

TABLE 1 Daily Dosage of L-Cysteine L-Cysteine L-Cysteine Protein^(a)Dosage Dosage Requirement (mg cysteine/ (mg cysteine/ Age (g/kg/day)¹ gAA) kg/day) Preterm and term infants 3 to 4 15 45 to 60 less than 1month of age Pediatric patients 1 month 2 to 3 15 30 to 45 to less than1 year of age Pediatric patients 1 year 1 to 2 15 15 to 30 to 11 yearsof age Pediatric patients 12 years 0.8 to 1.5  5   4 to 7.5 to 17 yearsof age Adults: Stable Patients 0.8 to 1    5 4 to 5 Adults: CriticallyIll Patients 1.5 to 2    5 7.5 to 10  ^(a)Protein is provided as aminoacids. When infused intravenously, amino acids are metabolized andutilized as the building blocks of protein.

From the above Table, it should be noted that the most need forL-Cysteine is for the preterm infant. Therefore, to safely administerL-Cysteine compositions, the Aluminum level in the compositions must besubstantially less than what is in commercially available products andthose described in the art. There has been no specific guidance in theart however of how low this Aluminum level should be, and how to achievecompositions with such low Aluminum levels. To the extent there may besome guidance, the levels proposed are considered higher than desirable.

L-Cysteine Injection as presented herein in some embodiments contains nomore than 120 mcg/L (120 ppb) of aluminum (0.0035 mcg of aluminum/mg ofcysteine). The maximum dosage of aluminum from L-Cysteine Injection isnot more than 0.21 mcg/kg/day when preterm and term infants less than 1month of age are administered the dosage of L-Cysteine injection (15 mgcysteine/g of amino acids and 4 g of amino acids/kg/day). If L-Cysteineis added to TPN containing amino acid and dextrose solutions (which eachmay contain up to 25 mcg/L of aluminum) as well as other additive drugproducts, the total amount of aluminum administered to the patient fromthe final admixture should be considered and maintained at no more than5 mcg/kg/day.

However, with prolonged parenteral administration in patients with renalimpairment, the aluminum contained in L-Cysteine Injections disclosedherein may reach toxic levels. Preterm infants are at a greater risk foraluminum toxicity because their kidneys are immature, and they requirelarge amounts of calcium and phosphate solutions, which also containaluminum. Prolonged administration herein may mean at least one week, ormay be up to 2-4 weeks. In some aspects, the administration couldcontinue for up to 24 weeks.

Patients with renal impairment, including preterm infants, who receiveparenteral levels of aluminum at greater than 4 to 5 mcg/kg/day,accumulate aluminum at levels associated with central nervous system andbone toxicity. Tissue loading may occur at even lower rates ofadministration. Therefore, it is essential that aluminum levels in theL-Cysteine drug product are carefully controlled and kept at as low aspossible. Such embodiments are disclosed herein.

Looking more specifically at contribution of Aluminum by the priorproducts, data show that the Aluminum levels of 5,000 ppb or even the900 ppb associated with these products are not desirable or acceptable.Tables 2-3 report the Aluminum contribution from the commercial productof prior art with 900 ppb or 5000 ppb Aluminum level based on twoscenarios: a) an L-Cysteine dosing regimen based on 15 mg/gram of aminoacids; and b) an L-Cysteine dosing regimen based on 40 mg/gram of aminoacids. The Tables also show the Aluminum contribution from an L-Cysteineproduct as described herein and having a level of 120 ppb.

TABLE 2 Aluminum Contribution (Based on a Cysteine Dose of 15 mg/g ofAmino Acids) from an L-Cysteine Product with 900 ppb, 5,000 ppb, or 120ppb of Aluminum Aluminum Aluminum Aluminum Contribution ContributionContribution L-Cysteine Dose at from 900 ppb from 5,000 from 120 ppb (15mg/g AA) product ppb product product Age mg/kg/day mL/kg/day mcg/kg/daymcg/kg/day mcg/kg/day Preterm and 45 to 60 1.31 to 1.74 1.18 to 1.576.53 to 8.70 0.157 to 0.209 term infants less than 1 month Pediatric 30to 45 0.87 to 1.31 0.79 to 1.17 4.35 to 6.52  0.1 to 0.157 patients 1month to less than 1 yr Pediatric 15 to 30 0.44 to 0.87 0.40 to 0.792.18 to 4.35 0.053 to 0.1  patients 1 yr to 11 yrs Pediatric   4 to 7.50.18 to 0.22 0.11 to 0.20 0.58 to 1.09 0.022 to 0.026 patients 12 yrs to17 yrs Adults: Stable 4 to 5 0.18 to 0.23 0.11 to 0.14 0.58 to 0.730.022 to 0.028 Patients Adults:  7 to 10 0.32 to 0.46  0.2 to 0.28 1.02to 1.46 0.038 to 0.055 Critically ill patients

TABLE 3 Aluminum Contribution (Based on a Cysteine Dose of 40 mg/g ofAmino Acids) from an L-Cysteine Product with 900 ppb, 5,000 ppb, or 120ppb of Aluminum Aluminum Aluminum Aluminum Contribution ContributionContribution L-Cysteine Dose at from 900 from 5,000 ppb from 120 ppb (40mg/g AA) ppb product product product Age mg/kg/day mL/kg/day mcg/kg/daymcg/kg/day mcg/kg/day Preterm and 120 to 160 3.48 to 4.64 3.13 to 4.1717.39 to 23.19 0.42 to 0.56 term infants less than 1 month Pediatric  80to 120 2.32 to 3.48 2.09 to 3.13 11.59 to 17.39 0.28 to 0.42 patients 1month to less than 1 yr Pediatric 40 to 80 1.16 to 2.32 1.05 to 2.09 5.79 to 11.59 0.14 to 0.28 patients 1 yr to 11 yrs Pediatric 10.66 to20   0.31 to 0.58 0.28 to 0.53 1.56 to 2.94 0.04 to 0.07 patients 12 yrsto 17 yrs Adults: Stable 10.66 to 13.33 0.31 to 0.39 0.28 to 0.35 1.56to 1.94  0.04 to 0.047 Patients Adults: 18.7 to 26.7 0.54 to 0.77 0.49to 0.70 2.72 to 3.89 0.065 to 0.09  Critically ill patients

If the preterm infants are given the high dose of L-cysteine (40 mg/gramof amino acids), this requires that a dose of 160 mg/kg (4.64 mL/kg) ofL-Cysteine at a (base) concentration of 34.5 mg/mL be delivered. (SeeTable 3 above). The compositions described herein contribute about0.0035 mcg Aluminum per each mg of L-cysteine, or 0.12 mcg of Aluminumper each mL at 120 ppb. Thus, a dose of 160 mg/kg (4.64 mL/kg)L-cysteine delivers only 0.56 mcg/kg Aluminum at 40 mg/g of AA dosing onthe higher end, or 0.157 mcg/kg at 15 mg/g of AA dosing on the lowerend. See Tables 2-3. In contrast, if art products were to be used, thesepatients would receive either 23 mcg/kg (for the product that contains5,000 ppb of Aluminum), or 4.2 mcg/kg of aluminum (for the product thatcontains 900 ppb of Aluminum). Given that the total daily intakepermissible for Aluminum is expected to be ideally less than 4-5 mcg/kg,the art products already exceed the entire daily Aluminum level and donot leave room for Aluminum contribution from other TPN components.Therefore, these known high Aluminum-containing products are likely tobe deemed unsafe by the FDA and are neither desirable nor acceptable. Incontrast, the L-Cysteine compositions presented herein provide Aluminumlevels ranging from 10 ppb to about 250 ppb. Taking 20 ppb, 50 ppb, 120ppb, and 150 ppb as illustrations, the Tables below estimate the amountof Aluminum delivered for each class of patients using 34.5 mg/mLL-Cysteine product when being dosed at 15 mg/g of Amino Acids.

TABLE 4 Aluminum Contribution (Based on a Cysteine Dose of 15 mg/g ofAmino Acids) from an L-Cysteine Product (34.5 mg/mL) with 20 ppb, 50ppb, 120 ppb or 150 ppb of Aluminum Aluminum Aluminum AluminumL-Cysteine Contribution Contribution Contribution Aluminum Dose at from20 ppb from 50 ppb from 120 ppb Contribution 15 mg/g AA product productproduct from 150 ppb Age mg/kg/day mcg/kg/day mcg/kg/day mcg/kg/daymcg/kg/day Preterm 45 to 60 0.026 to 0.035 0.065 to 0.088 0.157 to 0.2090.195 to 0.26  and term infants less than 1 month Pediatric 30 to 450.017 to 0.026 0.043 to 0.065  0.1 to 0.157  0.13 to 0.195 patients 1month to less than 1 yr Pediatric 15 to 30 0.009 to 0.017 0.022 to 0.0440.053 to 0.11  0.066 to 0.125 patients 1 yr to 11 yrs Pediatric   4 to7.5 0.004 0.009 to 0.01  0.022 to 0.026 0.027 to 0.033 patients 12 yrsto 17 yrs Adults: 4 to 5 0.004 0.009 to 0.12  0.022 to 0.028 0.027 to0.035 Stable Patients Adults:  7 to 10 0.006 to 0.009 0.016 to 0.23 0.038 to 0.055 0.048 to 0.069 Critically ill patients

In some embodiments, parenteral L-Cysteine compositions provide about 35mg/mL of L-Cysteine to deliver 45 to 60 mg/kg/day of L-Cysteine and fromabout 0.02 to about 0.3 mcg/kg/day of Aluminum. In some embodiments,parenteral L-Cysteine compositions provide about 35 mg/mL of L-Cysteineto deliver 30 to 45 mg/kg/day of L-Cysteine and from about 0.01 to about0.25 mcg/kg/day of Aluminum. In some embodiments, parenteral L-Cysteinecompositions provide about 35 mg/mL of L-Cysteine to deliver 15 to 30mg/kg/day of L-Cysteine and from about 0.005 to about 0.15 mcg/kg/day ofAluminum.

In some embodiments, parenteral L-Cysteine compositions provide about 35mg/mL of L-Cysteine to deliver 4 to 7.5 mg/kg/day of L-Cysteine and fromabout 0.003 to about 0.04 mcg/kg/day of Aluminum. In some embodiments,parenteral L-Cysteine compositions provide about 35 mg/mL of L-Cysteineto deliver 4 to 5 mg/kg/day of L-Cysteine and from about 0.003 to about0.04 mcg/kg/day of Aluminum. In some embodiments, parenteral L-Cysteinecompositions provide about 35 mg/mL of L-Cysteine to deliver 7 to 10mg/kg/day of L-Cysteine and from about 0.004 to about 0.08 mcg/kg/day ofAluminum.

In some embodiments, a method of safe administration of L-Cysteinecomprises administering to preterm and term infants of less than 1 monthof age a parenteral L-Cysteine composition that delivers 45 to 60mg/kg/day of L-Cysteine and from about 0.02 to about 0.3 mcg/kg/day ofAluminum, admixed with a parenteral nutrition composition. In someembodiments, a method of safe administration of L-Cysteine comprisesadministering to pediatric patients 1 month to less than 1 year of age aparenteral L-Cysteine composition that delivers 30 to 45 mg/kg/day ofL-Cysteine and from about 0.01 to about 0.25 mcg/kg/day of Aluminum,admixed with a parenteral nutrition composition. In some embodiments, amethod of safe administration of L-Cysteine comprises administering topediatric patients 1 year to 11 years of age a parenteral L-Cysteinecomposition that delivers 15 to 30 mg/kg/day of L-Cysteine and fromabout 0.005 to about 0.15 mcg/kg/day of Aluminum, admixed with aparenteral nutrition composition.

In some embodiments, a method of safe administration of L-Cysteinecomprises administering to pediatric patients 12 years to 17 years ofage a parenteral L-Cysteine composition that delivers 4 to 7.5 mg/kg/dayof L-Cysteine and from about 0.003 to about 0.04 mcg/kg/day of Aluminum,admixed with a parenteral nutrition composition. In some embodiments, amethod of safe administration of L-Cysteine comprises administering toadult stable patients a parenteral L-Cysteine composition that delivers4 to 5 mg/kg/day of L-Cysteine and from about 0.003 to about 0.04mcg/kg/day of Aluminum, admixed with a parenteral nutrition composition.In some embodiments, a method of safe administration of L-Cysteinecomprises administering to critically ill adult patients a parenteralL-Cysteine composition that delivers 7 to 10 mg/kg/day of L-Cysteine andfrom about 0.004 to about 0.08 mcg/kg/day of Aluminum, admixed with aparenteral nutrition composition.

Further, taking 20 ppb, 50 ppb, 120 ppb, and 150 ppb as illustrations,the Tables below estimate the amount of Aluminum delivered for eachclass of patients using 34.5 mg/mL L-Cysteine product when being dosedat 40 mg/g of Amino Acids.

TABLE 5 Aluminum Contribution (Based on a Cysteine Dose of 40 mg/g ofAmino Acids) from an L-Cysteine Product (34.5 mg/mL) with 20 ppb, 50ppb, 120 ppb or 150 ppb of Aluminum Aluminum Aluminum AluminumL-Cysteine Contribution Contribution Contribution Aluminum Dose at 40from 20 ppb from 50 ppb from 120 ppb Contribution mg/g AA productproduct product from 150 ppb Age mg/kg/day mcg/kg/day mcg/kg/daymcg/kg/day mcg/kg/day Preterm 120 to 160 0.07 to 0.09 0.175 to 0.2330.42 to 0.56 0.525 to 0.7  and term infants less than 1 month Pediatric 80 to 120 0.047 to 0.07  0.117 to 0.175 0.28 to 0.42  0.35 to 0.525patients 1 month to less than 1 yr Pediatric 40 to 80 0.023 to 0.0470.058 to 0.117 0.14 to 0.28 0.175 to 0.35  patients 1 yr to 11 yrsPediatric 10.66 to 20   0.007 to 0.012 0.017 to 0.029 0.04 to 0.07  0.05to 0.088 patients 12 yrs to 17 yrs Adults: 10.66 to 13.33 0.007 to 0.0080.017 to 0.02   0.04 to 0.047  0.05 to 0.059 Stable Patients Adults:18.7 to 26.7 0.011 to 0.015 0.027 to 0.038 0.065 to 0.09  0.081 to 0.113Critically ill patients

In some embodiments, parenteral L-Cysteine compositions provide about 35mg/mL of L-Cysteine to deliver 120 to 160 mg/kg/day of L-Cysteine andfrom about 0.05 to about 0.8 mcg/kg/day of Aluminum. In someembodiments, parenteral L-Cysteine compositions provide about 35 mg/mLof L-Cysteine to deliver 80 to 120 mg/kg/day of L-Cysteine and fromabout 0.03 to about 0.6 mcg/kg/day of Aluminum. In some embodiments,parenteral L-Cysteine compositions provide about 35 mg/mL of L-Cysteineto deliver 40 to 80 mg/kg/day of L-Cysteine and from about 0.01 to about0.4 mcg/kg/day of Aluminum.

In some embodiments, parenteral L-Cysteine compositions provide about 35mg/mL of L-Cysteine to deliver 10 to 20 mg/kg/day of L-Cysteine and fromabout 0.005 to about 0.1 mcg/kg/day of Aluminum. In some embodiments,parenteral L-Cysteine compositions provide about 35 mg/mL of L-Cysteineto deliver 10 to 15 mg/kg/day of L-Cysteine and from about 0.005 toabout 0.06 mcg/kg/day of Aluminum. In some embodiments, parenteralL-Cysteine compositions provide about 35 mg/mL of L-Cysteine to deliverabout 18 to 28 mg/kg/day of L-Cysteine and from about 0.01 to about 0.15mcg/kg/day of Aluminum.

In some embodiments, a method of safe administration of L-Cysteinecomprises administering to preterm and term infants of less than 1 monthof age a parenteral L-Cysteine composition that delivers 120 to 160mg/kg/day of L-Cysteine and from about 0.05 to about 0.8 mcg/kg/day ofAluminum, admixed with a parenteral nutrition composition. In someembodiments, a method of safe administration of L-Cysteine comprisesadministering to pediatric patients 1 month to less than 1 year of age aparenteral L-Cysteine composition that delivers 80 to 120 mg/kg/day ofL-Cysteine and from about 0.03 to about 0.6 mcg/kg/day of Aluminum,admixed with a parenteral nutrition composition. In some embodiments, amethod of safe administration of L-Cysteine comprises administering topediatric patients 1 year to 11 years of age a parenteral L-Cysteinecomposition that delivers 40 to 80 mg/kg/day of L-Cysteine and fromabout 0.01 to about 0.4 mcg/kg/day of Aluminum, admixed with aparenteral nutrition composition.

In some embodiments, a method of safe administration of L-Cysteinecomprises administering to pediatric patients 12 years to 17 years ofage a parenteral L-Cysteine composition that delivers 10 to 20 mg/kg/dayof L-Cysteine and from about 0.005 to about 0.1 mcg/kg/day of Aluminum,admixed with a parenteral nutrition composition. In some embodiments, amethod of safe administration of L-Cysteine comprises administering toadult stable patients a parenteral L-Cysteine composition that delivers10 to 15 mg/kg/day of L-Cysteine and from about 0.005 to about 0.06mcg/kg/day of Aluminum, admixed with a parenteral nutrition composition.In some embodiments, a method of safe administration of L-Cysteinecomprises administering to critically ill adult patients a parenteralL-Cysteine composition that delivers 18 to 28 mg/kg/day of L-Cysteineand from about 0.01 to about 0.15 mcg/kg/day of Aluminum, admixed with aparenteral nutrition composition.

Accordingly, what is provided herein, among other things, aretherapeutically and/or nutritionally effective amounts of L-cysteinewith significantly minimized risk of Aluminum toxicity.

I. Definitions

As used herein, the term “stable” refers to a composition that has thecomponent profiles described herein, for example, Aluminum, L-Cystine,and pyruvic acid, at the levels described and for the amount of timeidentified. In other words, a stable composition will contain thespecified levels of all components for sufficient period of time toenable the composition to be commercially manufactured, stored, shipped,and administered in a clinical setting. In general, products areconsidered stable if the period of time is three months, or three to sixmonths, or three to 12 months, or three to 15 months, or three to 18months or three to 24 months.

As used herein, the term “dissolved oxygen” refers to oxygen that isfound in the aqueous carrier of the compositions. Distinguished fromdissolved oxygen is the headspace oxygen. As used herein, the term“headspace oxygen” refers to the oxygen that is found in the headspacevolume of the sealed container comprising the composition.

As used herein, the term “cystine precipitate” refers to undissolvedL-cystine. The undissolved cystine may be visually detected asparticulate matter in solution.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a composition described herein. In one aspect, themammal may be a human.

The term “prophylaxis” or “prophylactic” refers to the continued absenceof symptoms of the disease or condition that would be expected had thecombination not been administered.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects, the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Compositions can take nearlyany physical state, including solid and/or liquid (i.e. solution).Furthermore, the term “dosage form” can include one or moreformulation(s) or composition(s) provided in a form suitable foradministration to a subject. As used herein, the term “compositions forinjection” and the like, refers to a composition that is intended forinjection, including dilution and admixing with other components priorto injection. Said injection may be administered as an intravenousinjection, or as an intravenous infusion. When administered asinfusions, the compositions may be administered through a peripheralvein in limited circumstances or more commonly through a central vein.One of skill in the art would have experience with such administrations.

As used herein, “effective amount” refers to an amount of an ingredient,such as L-cysteine, which, when included in a composition, is sufficientto achieve an intended compositional or physiological effect. Thus, a“therapeutically or nutritionally effective amount” refers to anon-toxic, but sufficient amount of an active agent, to achievetherapeutic or nutritional results in treating or preventing a conditionfor which the active agent is known to be effective or providingnutritional value to prevent effects of malnutrition. It is understoodthat various biological factors may affect the ability of a substance toperform its intended task. Therefore, an “effective amount” or a“therapeutically or nutritionally effective amount” may be dependent insome instances on such biological factors. Additionally, in some casesan “effective amount” or a “therapeutically or nutritionally effectiveamount” may not be achieved in a single dose. Rather, in some examples,an “effective amount” or a “therapeutically or nutritionally effectiveamount” can be achieved after administering a plurality of doses over aperiod of time, such as in a pre-designated dosing regimen. Further,while the achievement of therapeutic/nutritional effects may be measuredby a physician or other qualified medical personnel using evaluationsknown in the art, it is recognized that individual variation andresponse to treatments may make the achievement of therapeutic ornutritional effects a subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical and nutritional sciences as well as medicine.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of a component, or an action,characteristic, property, state, structure, item, or result. The exactallowable degree of deviation from absolute presence of such acomponent, or an action, characteristic, property, state, structure,item, or result may in some cases depend on the specific context.However, generally speaking, “substantially” will be so near as to havethe same overall result as if absolute and total extent or degree wereobtained. The use of “substantially” is equally applicable when used ina negative connotation to refer to the complete or near complete lack ofa component, or an action, characteristic, property, state, structure,item, or result. For example, a composition that is “substantially freeof” a component would either completely lack the component, or so nearlycompletely lack the component that the effect would be the same as if itcompletely lacked the component. In other words, a composition that is“substantially free of” an ingredient or element may still actuallycontain such component as long as there is no measurable effect thereof,for example, trace amounts. As used herein, “essentially free” means acomponent, or an action, characteristic, property, state, structure,item, or result is not present or is not detectable.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change,disorder or adverse health condition. For purposes of this disclosure,beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of the condition,stabilized (i.e., not worsening) state of the condition, delay orslowing of progression of the condition, amelioration or palliation ofthe condition, and absence of condition (whether partial or total),whether detectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, and/or the mammal being treated therewith. Thephrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a molecule. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule that acts as a counterion. The counterion may be any organic orinorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Hence, a pharmaceutically acceptable saltcan have one or more charged atoms and/or one or more counterions. Inthe case of L-cysteine, the hydrochloride salt form is preferred.

The phrase “single-use container” refers to a sealed pharmaceuticallyprepared container holding a drug product in a sterile environment thatis intended to be used in a single operation of transferring the entirecontents or substantially entire contents, wherein the transferoperation spans no more than 10-12 hrs, but often less than 8 hrs, oreven six hours. It should be recognized that the single-use container isgenerally preservative-free and that if multiple transfers areattempted, they should be completed in a short duration, i.e., less thanabout 8-10 hrs from the first breach of the sterile environment. In someaspects the single-use container may be used to administer all of itscontents to one subject in need thereof. In some aspects the single-usecontainer may be used to administer its contents to more than onesubject in need thereof.

As used herein, the term “mixing” refers to admixing, contacting,blending, stirring or allowing to admix, mix, blend, stir and the like.

As used herein, the term “safe” refers generally to a property of thecompositions and methods described herein relative to art method andcompositions and/or to FDA regulatory determination of the compositionsand methods as part of a therapeutically or nutritionally effectiveregimen. For example, with respect to known L-Cysteine compositions, anAluminum level of greater than 300 ppb would be generally considered torender the L-Cysteine product unsafe. Other examples with respect tosafety are described and discussed herein with respect to Aluminum,pyruvate, Cystine, heavy metals, anions, and particulates.

Additional definitions are provided herein where appropriate.

II. Compositions

In certain aspects, the subject matter described herein is directed to asafe, stable L-cysteine composition for parenteral administration,comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof in an amount from about 10 mg/mL to about 100 mg/mL;

Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) toabout 250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

a pharmaceutically acceptable carrier, comprising water;

headspace O₂ that is from about 0.5% to 4.0% from the time ofmanufacture to about 1 month from manufacture when stored at roomtemperature;

dissolved oxygen present in the carrier in an amount from about 0.1parts per million (ppm) to about 5 ppm from the time of manufacture toabout 1 month from manufacture when stored at room temperature;

wherein the composition is enclosed in a single-use container having avolume of from about 10 mL to about 100 mL.

In certain aspects, the subject matter described herein is directed to asafe, stable L-cysteine composition for parenteral administration,comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof in an amount from about 10 mg/mL to about 100 mg/mL;

Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) toabout 250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

a pharmaceutically acceptable carrier, comprising water;

headspace O₂ that is from about 0.5% to 4.0% from the time ofmanufacture to about 1 month from manufacture when stored at roomtemperature;

dissolved oxygen present in the carrier in an amount from about 0.1parts per million (ppm) to about 5 ppm from the time of manufacture toabout 1 month from manufacture when stored at room temperature;

optionally present can be one or more metals selected from the groupconsisting of Lead from about 1.0 ppb to about 10 ppb, Nickel from about5 ppb to about 40 ppb, Arsenic from about 0.1 ppb to 10 ppb, and Mercuryfrom about 0.2 ppb to about 5.0 ppb;

wherein the composition is enclosed in a single-use container having avolume of from about 10 mL to about 100 mL.

The Aluminum in a composition can be determined using any knownanalytical method, such as those required by FDA regulations, and caninclude atomic absorption and mass spectrometry. In certain embodiments,the Aluminum that is present in the compositions is present in an amountfrom about 1.0 ppb to about 250 ppb, or from about 1.0 ppb to about 180ppb, or from about 1.0 ppb to about 170 ppb, or from about 1.0 ppb toabout 160 ppb, or from about 1.0 ppb to about 150 ppb, or from about 1.0ppb to about 130 ppb, or from about 1.0 ppb to about 100 ppb, or fromabout 1.0 ppb to about 50 ppb, or from about 1.0 ppb to about 20 ppb.

In some embodiments the L-Cysteine and Aluminum are at a ratio of fromabout 35 million:1 (i.e., about 35 million units of L-Cysteine to 1 unitof Aluminum). In some embodiments the L-Cysteine and Aluminum are at aratio of about 4 million:1. In some embodiments the L-Cysteine andAluminum are at a ratio of about 1.8 million:1 (i.e., about 1.8 millionunits of L-Cysteine to 1 unit of Aluminum). In some embodiments theL-Cysteine and Aluminum are at a ratio of about 700,000:1 (i.e., about700,000 units of L-Cysteine to 1 unit of Aluminum). In some embodimentsthe L-Cysteine and Aluminum are at a ratio of about 300,000:1 (i.e.,about 300,000 units of L-Cysteine to 1 unit of Aluminum). In someembodiments the L-Cysteine and Aluminum are at a ratio of about230,000:1 (i.e., about 230,000 units of L-Cysteine to 1 unit ofAluminum). In some embodiments the L-Cysteine and Aluminum are at aratio of about 170,000:1 (i.e., about 170,000 units of L-Cysteine to 1unit of Aluminum). In some embodiments the L-Cysteine and Aluminum areat a ratio of about 140,000:1 (i.e., about 140,000 units of L-Cysteineto 1 unit of Aluminum).

Thus, in some embodiments the L-Cysteine and Aluminum are at a ratio offrom about 35 million:1 (i.e., about 35 million units of L-Cysteine to 1unit of Aluminum) to about 1.8 million:1 (i.e., about 1.8 million unitsof L-Cysteine to 1 unit of Aluminum). In some embodiments the L-Cysteineand Aluminum are at a ratio of from about 4 million:1 (i.e., about 4million units of L-Cysteine to 1 unit of Aluminum) to about 1.8million:1 (i.e., about 1.8 million units of L-Cysteine to 1 unit ofAluminum). In some embodiments the L-Cysteine and Aluminum are at aratio of from about 1.8 million:1 (i.e., about 1.8 million units ofL-Cysteine to 1 unit of Aluminum) to about 700,000:1 (i.e., about700,000 units of L-Cysteine to 1 unit of Aluminum). In some embodimentsthe L-Cysteine and Aluminum are at a ratio of from about 700,000:1(i.e., about 700,000 units of L-Cysteine to 1 unit of Aluminum) to about300,000:1 (i.e., about 300,000 units of L-Cysteine to 1 unit ofAluminum). In some embodiments the L-Cysteine and Aluminum are at aratio of from about 300,000:1 (i.e., about 300,000 units of L-Cysteineto 1 unit of Aluminum) to about 230,000:1 (i.e., about 230,000 units ofL-Cysteine to 1 unit of Aluminum). In some embodiments the L-Cysteineand Aluminum are at a ratio of from about 230,000:1 (i.e., about 230,000units of L-Cysteine to 1 unit of Aluminum) to about 170,000:1 (i.e.,about 170,000 units of L-Cysteine to 1 unit of Aluminum). Thus, in someembodiments the L-Cysteine and Aluminum are at a ratio of from about170,000:1 (i.e., about 170,000 units of L-Cysteine to 1 unit ofAluminum) to about 140,000:1 (i.e., about 140,000 units of L-Cysteine to1 unit of Aluminum). All subranges and individual values with incrementsof 5,000 units are contemplated by the present disclosure. In someembodiments, the unit of measure is nanograms. For example, in someembodiments the L-Cysteine and Aluminum are at a ratio of from about 4million:1 nanograms (i.e., about 4 million nanograms of L-Cysteine to 1nanogram of Aluminum) to about 1.8 million:1 nanograms (i.e., about 1.8million nanograms of L-Cysteine to 1 nanogram of Aluminum).

In certain embodiments, the compositions comprise Aluminum in traceamounts, for example 1.0 ppb, but not more than 250 ppb after storage atambient temperature for a period of 12 months or less, where theAluminum comprises, from about 1.0 ppb to about 100 ppb of Aluminum fromthe container, from about 1.0 ppb to about 100 ppb of Aluminum from acap of the container, from about 1.0 ppb to about 100 ppb of Aluminumfrom the L-cysteine, and from about 1.0 ppb to about 20 ppb of Aluminumfrom the water.

In certain embodiments, the compositions comprise Aluminum in an amountnot more than 200 ppb after storage at ambient temperature for a periodof 12 months, wherein the Aluminum comprises, from about 1.0 ppb toabout 100 ppb of Aluminum from the container, from about 1.0 ppb toabout 100 ppb of Aluminum from a cap of the container, from about 1.0ppb to about 100 ppb of Aluminum from the L-cysteine, and from about 1.0ppb to about 20 ppb of Aluminum from the water. In certain embodiments,the compositions comprise Aluminum in an amount not more than 200 ppbafter storage at ambient temperature for a period of 6 months, where theAluminum comprises, from about 1.0 ppb to about 100 ppb of Aluminum fromthe container, from about 1.0 ppb to about 100 ppb of Aluminum from acap of the container, from about 1.0 ppb to about 100 ppm of Aluminumfrom the L-cysteine, and from about 1.0 ppb to about 20 ppb of Aluminumfrom the water. In certain embodiments, the compositions compriseAluminum in an amount not more than 200 ppb after storage at ambienttemperature for a period of 3 months, wherein the Aluminum comprises,from about 1.0 ppb to about 100 ppb of Aluminum from the container, fromabout 1.0 ppb to about 100 ppb of Aluminum from a cap of the container,from about 1.0 ppb to about 100 ppm of Aluminum from the L-cysteine, andfrom about 1.0 ppb to about 20 ppb of Aluminum from the water.

In certain embodiments, the dissolved oxygen is present in an amountfrom about 0.1 ppm to about 5.0 ppm, or from about 0.10 ppm to about 4.0ppm, or from about 0.10 ppm to about 3.0 ppm, or from about 0.10 ppm toabout 2.0 ppm, or from about 0.11 ppm to about 1.0 ppm. In particular,values of dissolved oxygen from about 0.4 ppm to about 3.8 ppm arepreferred. For the sake of clarity and the ease of discussion andmeasurement, these values are taken for the L-Cysteine composition atthe time of its manufacture (commonly known as “time zero” data point),or during and up to 1 month from time zero. Additional time pointsbeyond the 1-month from time zero data point are expected to providesimilar dissolved oxygen levels.

To achieve the above objective, as described herein, numerous aspectsfor possible oxygen introduction into the L-cysteine composition havebeen carefully studied and controlled. For example, in some cases, thedissolved oxygen content in the carrier can be reduced to at or below apredetermined level before the L-cysteine is added to the carrier. Insome additional examples, reducing a level of dissolved oxygen in thecarrier can include blanketing a container for housing the compositionin an inert gas, such as nitrogen, argon, or the like, prior tointroducing the carrier or composition into the container. In stillother examples, reducing a level of dissolved oxygen in the carrier caninclude bubbling the carrier or composition with an inert gas, such asnitrogen, argon, or the like, at ambient or reduced atmospheric pressureprior to and/or during addition and mixing of L-cysteine. In someexamples, reducing a level of dissolved oxygen in the carrier can beperformed at an ambient or sub-ambient temperature. It is noted that thereduction of dissolved oxygen in the carrier to at or below apredetermined level can be accomplished without the addition of asupplementary antioxidant, but is not required in the methods andcompositions described herein. Thus, the L-cysteine composition forinjection is free of a supplementary antioxidant. As described elsewhereherein, attaining low and consistent dissolved oxygen was achieved usingthe protocol with sampling as set forth in Example 4.

The compositions have long-term stability. Thus, in certain embodiments,the amounts of the components described herein are amounts that aredetected after the composition has been in storage. The compositionswill have been stored at room temperature for less than a year, or for ayear, or for more than a year. Such timelines include, for example, forabout 15 months, for about 18 months, for about 24 months. Or,alternatively, the storage time could be for about 9 months, for about 7months, for about 6 months, for about 5 months, for about 4 months, forabout 3 months, for about 2 months, for about 1 month, or for about 3weeks. Storage conditions are 25° C./60% RH unless otherwise indicated.

Useful concentrations of L-cysteine or a pharmaceutically acceptablesalt thereof and/or hydrate thereof in a compositions as describedherein include an amount from about 20 mg/mL to about 80 mg/mL, fromabout 30 mg/mL to about 70 mg/mL, from about 40 mg/mL to about 60 mg/mL,from about 45 mg/mL to about 55 mg/mL, or an amount of about 50 mg/mL,or from about 35 mg/mL to about 50 mg/mL, or an amount of about 37.5mg/mL. It is noted that the amounts of L-cysteine disclosed herein,whether as a total mass or as a concentration, are based on L-cysteinehydrochloride monohydrate or the free base, as specified. Thus, whereother forms of L-cysteine are employed in the composition, the amount ofthe alternative form included in the composition can be calculated basedon an equivalent amount of L-cysteine hydrochloride monohydrate ratherthan the amount of the alternative form employed.

Thus, the stable L-cysteine composition can comprise total amounts ofL-cysteine from about 200 mg to about 4000 mg, or from about 300 mg toabout 700 mg, or from about 300 mg to about 400 mg. For example, a 10 mLvial could be manufactured to contain about 350 mg of L-Cysteine. Incertain embodiments, the L-cysteine composition can comprise a totalamount of L-cysteine from about 1200 mg to about 2000 mg. For example, a50 mL container could be manufactured to contain about 1800 mg ofL-Cysteine. In another embodiment, the total composition of anL-Cysteine composition container may range from about 3000 mg to about4000 mg. For example, a 100 mL container could be manufactured tocontain about 3500 mg of total L-Cysteine.

It has been found that the container in which the compositions are heldcan affect the level of certain components. In certain embodiments, theL-cysteine composition can be enclosed in a single-use container. Thecontainer can have a variety of volumes. Typically, the container canhave a volume of from about 10 ml to about 100 ml. In some examples, thecontainer can have a volume of from about 10 ml to about 50 ml. In otherexamples, the container can have a volume of from about 50 ml to about100 ml. In still other examples, the container can have a volume ofabout 10 ml or about 20 ml.

The container can be made of a variety of materials. Non-limitingmaterials can include glass, a plastic (e.g. polyethylene,polypropylene, polyvinyl chloride, polycarbonate, etc.), the like, or acombination thereof provided that it can both prevent oxygen penetrationand minimize Aluminum, heavy metals and anions contamination to thecomposition. Up to now, there has been no guidance with regard to thecompatibility of L-cysteine with coated glass vials or that any vialscould be used to provide L-cysteine compositions having low levels ofAluminum.

Another confounding factor is the low pH of the L-Cysteine product,which is less than 3.0 in certain embodiments. This low pH can disruptthe plastic coating or silicon coating inside the glass container andAluminum, heavy metals and anions could leach during the shelf life ofthe product, especially over prolonged storage of the product.Therefore, up to now, the success of the product was uncertain until theproducts described herein were manufactured and studied in real time forprolonged periods as described herein.

It should be recognized that vials which are impermeable with aninternal coating, vials which are stored in a pouch that protects theproduct from atmospheric oxygen ingress, and relatively thick vials madeof impermeable plastic or glass can be suitable for the L-Cysteineproduct disclosed herein.

Vials which are stored in a pouch can be prepared in a similar manner asdescribed herein and then pouched in a plastic material that is thensealed. The pouch may be kept under vacuum or under an inert atmosphere.Methods for manufacturing such pouched products, and materials for suchmanufacture are known in the industry.

Relatively thick vials made of impermeable plastic are also prepared ina similar manner as described herein. Such vials may be composed ofcyclic olefin materials of sufficient thickness to prevent oxygeningress over a reasonably long period of time, for example 1 month, 2months, 3 months, 6 months or 12 months. These vials are packaged andsupplied as such. Alternatively, these vials can also be pouched asdescribed above in plastic material that is kept under vacuum or underan inert gas atmosphere. It is expected that such pouching extends theshelf life of the product by at least 1 month, or 2 months, or 3 months,or 6 months or longer.

In certain embodiments, the vials are made of glass with an internalcoating made of silicon dioxide, for example, Schott Type 1 Plus USPglass. The general thickness of the coating is presumed to be at least100-200 nanometers thickness. It is believed that this level ofthickness was sufficient to provide protection against pH disruptionwhile also preventing the migration of Aluminum from the glass into theL-Cysteine product. Thus, in some specific examples, the container canbe an internally coated glass container. In certain other embodimentsthe glass container is internally coated with silicon dioxide of about100 to about 200 nanometers.

In certain embodiments the Aluminum contribution from the container mayrange from about 0.1 ppb to about 200 ppb. In certain other embodimentsthe Aluminum contribution may range from about 1 ppb to about 150 ppb,from about 1 ppb to about 120 ppb, from about 1 ppb to about 100 ppb,from about 1 ppb to about 80 ppb, from about 1 ppb to about 60 ppb, fromabout 1 ppb to about 50 ppb, from about 1 ppb to about 40 ppb, fromabout 1 ppb to about 30 ppb, from about 1 ppb to about 25 ppb, fromabout 1 ppb to about 20 ppb, from about 1 ppb to about 15 ppb, fromabout 1 ppb to about 10 ppb, from about 1 ppb to 5 ppb. In certainembodiments, the contribution could be in subranges within the aboveranges, for example, from about 35 to 55 ppb, or from about 75 to about140 ppb, in increments of 5 ppb. All such ranges and subranges arecontemplated herein.

The containers are sealed with a suitable stopper made of rubber,elastomeric polymers, or combinations thereof. In certain embodimentsthe stoppers are coated with a special non-reactive inert coating thatminimizes interaction with drug product. For example, some stoppers arecoated with Teflon to prevent drug-stopper interactions. One example ofa specific coated stopper is supplied by West Pharma and is calledV10-F597W Stopper, 20 mm Lyo, 4432/50 Gray, B2-TR Coating, Westar RS.This stopper is a cross-linked mixture of high- and low-molecular weightsilicone oils that are cured through the application of UV rays andheat. Because it is a spray-on coating applied to molded closures beforethe trimming process, B2-Coating can be applied at various levels on thebottom and top of closures. These specific stoppers are preferred eventhough similar coating materials and methodology applied to other typesof stoppers could also work. The stoppers are selected not only fortheir inertness vis-à-vis the drug product but also for their minimalcontribution to Aluminum levels in the drug product.

In certain embodiments the Aluminum contribution from the stopper mayrange from about 0.1 ppb to about 100 ppb. In certain other embodimentsthe Aluminum contribution may range from about 1 ppb to about 90 ppb,from about 1 ppb to about 80 ppb, from about 1 ppb to about 70 ppb, fromabout 1 ppb to about 60 ppb, from about 1 ppb to about 50 ppb, fromabout 1 ppb to about 40 ppb, from about 1 ppb to about 30 ppb, fromabout 1 ppb to about 25 ppb, from about 1 ppb to about 20 ppb, fromabout 1 ppb to about 15 ppb, from about 1 ppb to about 10 ppb, fromabout 1 ppb to 5 ppb. In certain embodiments, the contribution could bein subranges within the above ranges, for example, from about 35 to 55ppb, or from about 25 to about 75 ppb, in increments of 5 ppb. All suchranges and subranges are contemplated herein.

In addition to the container and stopper, the drug substance andexcipients including water for injection may contribute Aluminum to thedrug product. Thus, in one aspect the Aluminum contribution from thedrug substance may range from about 0.1 ppb to about 70 ppb. In certainother embodiments the Aluminum contribution may range from about 1 ppbto about 60 ppb, from about 1 ppb to about 50 ppb, from about 1 ppb toabout 40 ppb, from about 1 ppb to about 30 ppb, from about 1 ppb toabout 25 ppb, from about 1 ppb to about 20 ppb, from about 1 ppb toabout 15 ppb, from about 1 ppb to about 10 ppb, from about 1 ppb to 5ppb. In certain embodiments, the contribution could be in subrangeswithin the above ranges, for example, from about 35 to 55 ppb, or fromabout 75 to about 140 ppb, in increments of 5 ppb. All such ranges andsubranges are contemplated herein.

The water for injection may contribute Aluminum from about 0.1 ppb toabout 20 ppb. In certain embodiments the Aluminum contribution may rangefrom about 1 ppb to about 15 ppb, from about 1 ppb to about 12 ppb, fromabout 1 ppb to about 10 ppb, from about 1 ppb to about 8 ppb, from about1 ppb to about 6 ppb, from about 1 ppb to about 5 ppb, from about 1 ppbto about 4 ppb, from about 1 ppb to about 3 ppb, from about 1 ppb toabout 2.5 ppb, from about 1 ppb to about 2 ppb, from about 1 ppb toabout 1.5 ppb. In certain embodiments, the contribution could be insubranges within the above ranges, for example, from about 5 to 7.5 ppb,or from about 10.5 to about 15.0 ppb, in increments of 0.5 ppb. All suchranges and subranges are contemplated herein.

In summary, to lower the Aluminum level to even greater extent asdescribed herein, the container, the stopper, the drug substance, thewater for injection, and any other excipients can be chosen such thatthe Aluminum concentration in the drug product is from about 1.0 ppb toabout 250 ppb, or as described in the other embodiments provided herein.

Advantageously, in certain embodiments, the compositions maintaincystine levels for extended periods, and/or are substantially free oressentially free of cystine precipitate. However, it is noted that wherecystine is present in the L-cysteine composition it is not necessarilydissolved. For example, in some cases, it can be present in thecomposition as an undissolved particle.

Where the L-cysteine composition includes cystine, it can typically bepresent in relatively small amounts compared to L-cysteine. In certainembodiments, cystine is present in the composition in an amount not morethan 2.0 wt % relative to L-cysteine after storage at ambienttemperature for a period of 6 months. In certain embodiments, cystine ispresent in the composition in an amount not more than 1.0 wt % relativeto L-cysteine after storage at ambient temperature for a period of 6months. In certain embodiments, cystine is present in the composition inan amount not more than 0.5 wt % relative to L-cysteine after storage atambient temperature for a period of 6 months. In certain embodiments,cystine is present in the composition in an amount not more than 0.4 wt% relative to L-cysteine after storage at ambient temperature for aperiod of 6 months. In certain embodiments, cystine is present in thecomposition in an amount not more than 0.3 wt % relative to L-cysteineafter storage at ambient temperature for a period of 6 months. Incertain embodiments, cystine is present in the composition in an amountnot more than 0.2 wt % relative to L-cysteine after storage at ambienttemperature for a period of 6 months. In certain embodiments, cystine ispresent in the composition in an amount not more than 0.1 wt % relativeto L-cysteine after storage at ambient temperature for a period of 6months.

Further, in certain embodiments, cystine can be present in theL-cysteine composition, but in an amount not more than 2.0 wt % relativeto L-cysteine after storage at ambient temperature for a period of 3months. In certain embodiments, cystine can be present in the L-cysteinecomposition, but in an amount not more than 2.0 wt % relative toL-cysteine after storage at ambient temperature for a period of 3months. In some embodiments, cystine can be present in the L-cysteinecomposition in an amount from about 0.001 wt % to about 2.0 wt %relative to the amount of L-cysteine present in the composition. In someembodiments, cystine can be present in the L-cysteine composition in anamount from about 0.005 wt % to about 0.5 wt % relative to the amount ofL-cysteine present in the composition. In some embodiments, cystine canbe present in the L-cysteine composition in an amount from about 0.05 wt% to about 1.0 wt % relative to the amount of L-cysteine present in thecomposition. In some embodiments, L-cystine can be present, but in anamount that is either not detectable or that is below a limit ofquantitation using a standard testing procedure, such as a validatedtest method for detecting cystine.

Advantageously, in certain embodiments, the compositions maintainpyruvic acid levels for extended periods, and/or are substantially freeor essentially free of pyruvic acid. When present, pyruvic acid istypically present in a relatively small amount compared to L-cysteine.In certain embodiments, pyruvic acid is present in the composition in anamount not more than 2.0 wt % relative to L-cysteine after storage atambient temperature for a period of 6 months. In certain embodiments,pyruvic acid is present in the composition in an amount not more than1.0 wt % relative to L-cysteine after storage at ambient temperature fora period of 6 months. In certain embodiments, pyruvic acid is present inthe composition in an amount not more than 0.5 wt % relative toL-cysteine after storage at ambient temperature for a period of 6months. In certain embodiments, pyruvic acid is present in thecomposition in an amount not more than 0.4 wt % relative to L-cysteineafter storage at ambient temperature for a period of 6 months. Incertain embodiments, pyruvic acid is present in the composition in anamount not more than 0.3 wt % relative to L-cysteine after storage atambient temperature for a period of 6 months. In certain embodiments,pyruvic acid is present in the composition in an amount not more than0.2 wt % relative to L-cysteine after storage at ambient temperature fora period of 6 months.

In certain embodiments, pyruvic acid is present in the composition in anamount not more than 0.1 wt % relative to L-cysteine after storage atambient temperature for a period of 6 months. In certain embodiments,pyruvic acid can be present in the L-cysteine composition, but in anamount not more than 2.0 wt % relative to L-cysteine after storage atambient temperature for a period of 3 months. In certain embodiments,pyruvic acid can be present in the L-cysteine composition, but in anamount not more than 2.0 wt % relative to L-cysteine after storage atambient temperature for a period of 6 months. In some embodiments,pyruvic acid can be present in the L-cysteine composition in an amountfrom about 0.001 wt % to about 2.0 wt % relative to the amount ofL-cysteine present in the composition. In some embodiments, pyruvic acidcan be present in the L-cysteine composition in an amount from about0.005 wt % to about 0.5 wt % relative to the amount of L-cysteinepresent in the composition. In some embodiments, pyruvic acid can bepresent in the L-cysteine composition in an amount from about 0.05 wt %to about 1.0 wt % relative to the amount of L-cysteine present in thecomposition. In some embodiments, pyruvic acid can be present, but in anamount that is either not detectable or that is below a limit ofquantitation using a standard testing procedure, such as a validatedtest method for detecting pyruvic acid.

As discussed above, to achieve safe method and compositions, it isbeneficial to further understand which other components are presentbeyond Aluminum and pyruvic acid, and control their amounts as well.Because preterm infants could be exposed to L-Cysteine for potentiallylonger periods, and their main source of L-Cysteine is throughparenteral administration, careful consideration should be given toexposure to other potentially unsafe compounds that may leach out of thecontainer or stopper in amounts greater than what are considered safelimits. Examples include certain volatile compounds, certain heavyelements, and certain anions.

Daily acceptable limits are known for these potentially unsafecompounds. However, because the L-Cysteine Injection is used to infuseinto preterm and term infants and those elderly that are critically illwill compromised renal functions, and sometimes for periods that exceedmore than a few days, just meeting the daily acceptable limits may notbe sufficient. Every effort must be made to reduce the levels to as lowas practicable. The L-Cysteine compositions presented herein provide insome embodiments about one-half of the daily acceptable limits; in someembodiments, about one-fourth of the daily acceptable limits; in someembodiments, about one-fifth of the daily acceptable limits; in someembodiments, about one-sixth of the daily acceptable limits.

The anions that are desirable to control are: Iodide and Fluoride. Theacceptable limit for Iodide is about 20 ppm or less. The acceptablelimit for Fluoride is about 30 ppm or less. The L-Cysteine compositionsprovided herein show Iodide concentrations of less 20 ppm and Fluorideconcentrations of less than 30 ppm when measured at any time from theday of manufacture through its shelf-life of 6 months, or 12 months, or18 months, or 24 months, when stored under Room Temperature Conditions.In some embodiments, the L-Cysteine compositions provide from about 1.0ppm to 20 ppm of Iodide; in some embodiments, from about 1.0 ppm toabout 15 ppm; in some embodiments, from about 1.0 ppm to about 10 ppm;and in some embodiments, from about 1.0 ppm to about 5 ppm. In someembodiments, the L-Cysteine compositions provide from about 1.0 ppm to20 ppm of Fluoride; in some embodiments, from about 1.0 ppm to about 15ppm; in some embodiments, from about 1.0 ppm to about 10 ppm; and insome embodiments, from about 1.0 ppm to about 5 ppm. Methods forevaluating the anions and the results are provided in Example 8.

As noted above, several elements may leach or be extracted out into theL-Cysteine drug product, thereby presenting a potential safety/toxicityconcern to subjects that require L-Cysteine parenteral administration.Art-known methods may be used to evaluate the elemental levels.Inductively-coupled plasma mass spectral method is one such highlyspecific method. Example 9 provides the data generated by using ICP-MStechnique. As shown in Example 9, there are over thirty elements thatare generally known to present safety/toxicity concerns. The Table 22provides the daily allowable limit for all of these elements, and theobserved levels in the present L-Cysteine compositions. The dailyallowable limit for some elements are relatively high, whereas for otherelements they are relatively very low. For example, Molybdynum has thelevel of 14,500 ppb approximately, whereas Cadmium has about 19 ppb.

For purposes of monitoring the L-Cysteine compositions for the elementsof concern, in one aspect, the levels of Mercury, Lead, Nickel andArsenic are of significance. Therefore, in one aspect, the L-Cysteinecompositions presented herein have further improved safety because theyprovide these elements at amounts far less than the daily allowablelimits. Targeted daily allowable limits include 48 ppb for Lead, 29 ppbfor Mercury, 194 ppb for Nickel, and 174 ppb for Arsenic.

The L-Cysteine compositions described herein provide from about 1 ppb to10 ppb of Lead; in some embodiments, from about 1 ppb to about 8 ppb; insome embodiments, from about 1 ppb to about 7 ppb; or in someembodiments, from about 1 ppb to about 5 ppb. when measured at any timefrom the day of manufacture through its shelf-life of 6 months, or 12months, or 18 months, or 24 months, when stored under Room TemperatureConditions.

With respect to Mercury, the L-Cysteine compositions described hereinprovide from about 0.1 ppb to 10 ppb of Mercury; in some embodiments,from about 0.1 ppb to about 8 ppb; in some embodiments, from about 0.1ppb to about 7 ppb; or in some embodiments, from about 0.1 ppb to about5 ppb. when measured at any time from the day of manufacture through itsshelf-life of 6 months, or 12 months, or 18 months, or 24 months, whenstored under Room Temperature Conditions.

With respect to Nickel, the L-Cysteine compositions described hereinprovide from about 1 ppb to 50 ppb of Nickel; in some embodiments, fromabout 1 ppb to about 40 ppb; in some embodiments, from about 1 ppb toabout 30 ppb; or in some embodiments, from about 1 ppb to about 25 ppb;or in some embodiments from about 1 ppb to about 20 ppb, when measuredat any time from the day of manufacture through its shelf-life of 6months, or 12 months, or 18 months, or 24 months, when stored under RoomTemperature Conditions.

With respect to Arsenic, the L-Cysteine compositions described hereinprovide from about 0.1 ppb to 60 ppb of Arsenic; in some embodiments,from about 0.1 ppb to about 50 ppb; in some embodiments, from about 0.1ppb to about 40 ppb; in some embodiments, from about 0.1 ppb to about 30ppb; in some embodiments, from about 0.1 ppb to about 25 ppb; or in someembodiments from about 0.1 ppb to about 20 ppb; in some embodiments,from about 0.1 ppb to about 15 ppb; in some embodiments, from about 0.1ppb to about 10 ppb; or in some embodiments, from about 0.1 ppb to about5.0 ppb, when measured at any time from the day of manufacture throughits shelf-life of 6 months, or 12 months, or 18 months, or 24 months,when stored under Room Temperature Conditions.

In some embodiments, the Arsenic, Mercury, Lead and other elements maybe extracted from the container or from the stopper. In one specificembodiment, the extracted out amount of Arsenic, Mercury, Lead, andNickel combined from the stopper is 100 ppb or less. In otherembodiments, the extracted amount of Arsenic, Mercury, Lead, and Nickelcombined from the stopper is from about 10 to about 50 or from about 10to about 100 ppb.

It should be recognized that in some instances the amount of a specificelement present in the L-Cysteine compositions described herein may bebelow the Limit of Quantitation (LOQ). In those instances, for purposesof this disclosure and claims made herein, the compositions may beconsidered to contain the lowest level described in the precedingparagraphs. For example, when Arsenic is determined to be below the LOQ,the Arsenic amount may be considered to be at 0.1 ppb. Therefore, allsuch instances where the compositions show amounts below the LOQ arewithin the contemplation of this disclosure.

In certain embodiments, the compositions further comprise within thecontainer, headspace gas that includes oxygen in an amount of from about0.5% v/v to about 5.0% v/v, or from about 0.5% v/v to about 4.0% v/v, orfrom about 0.5% v/v to about 3.5% v/v, from about 0.5% v/v to about 3.0%v/v, or from about 0.5% v/v to about 2.5% v/v, or from about 0.5% v/v toabout 2.0% v/v, or from about 0.5% v/v to about 1.5% v/v, or from about0.5% v/v to about 1.0% v/v, or in some cases from about 0.1% v/v toabout 0.5% v/v, or from about 0.1% v/v to about 0.4% v/v, or from about0.1% v/v to about 0.3% v/v, or from about 0.1% v/v to about 0.2% v/v.For the sake of clarity and the ease of discussion and measurement,these values are taken for the L-Cysteine composition at the time of itsmanufacture (“tine zero” data point), or during and up to 1 month fromtime zero. Additional time points beyond the 1-month from time zero datapoint may provide similar headspace oxygen levels.

Without wishing to be bound by theory, the dissolved oxygen levels andthe head space oxygen levels within a sealed container of L-Cysteinecompositions described herein may reach an equilibrium at some timepoint during its shelf-life. Such equilibrium may be maintained for avery short time, i.e., for a few seconds, or for a very long time, i.e.,for several months. Such equilibrium may on occasion be disturbed bysimple agitation. Therefore, it should be recognized that dissolvedoxygen levels and headspace oxygen levels may fluctuate from one timepoint to another in terms of absolute numbers. However, the numbers areexpected to stay within the ranges disclosed herein. Occasionally, onenumber (e.g., dissolved oxygen) may exceed or fall out of a certainrange (e.g., from about 05 to about 3.0 PPM) at a 15-day time point, butmay fall within that range at some other time point (e.g., 30 day timepoint, or later). Therefore, in some aspects, the ranges, subranges, andspecific data points disclosed and discussed herein are valid andsuitable for time points beyond the time zero and 1-month time points.In one aspect, the time points could be extended to 2-months, 3-months,6-months, 9-months, 12-months, 15-months, 18-months, and 24 months.

In some aspects, the total amount of oxygen in the sealed container maybe an appropriate measure to evaluate the stability of the L-Cysteinecompositions herein. For example, the total amount of oxygen within thecontainer may be arrived at by adding up the amount of dissolved oxygenin the carrier and the amount of head space oxygen. These values canalso be expressed independently in separate units (i.e., dissolvedoxygen as ppm and head space oxygen as % v/v). An example would be anL-Cysteine composition that contains a dissolved oxygen level of fromabout 0.1 ppm to 4.0 ppm and a head space oxygen level of about 0.5% v/vto about 4.0% v/v.

The amount of oxygen present in the headspace of the container can becontrolled by filling the headspace with an inert gas, such as nitrogenor argon. Alternatively, the head space oxygen may be controlled byvacuum operation without using an inert gas. In another aspect, the headspace oxygen may be controlled by a combination of vacuum operation andinert gas overlay. In one particular aspect, the head space oxygen iscontrolled by repeated pulses of vacuum and inert gas overlay in tandemsuch that the process may start first with vacuum operation followed byinert gas overlay followed by vacuum operation. The combination ofvacuum operation and inert gas overlay (or inert gas overlay and vacuumoperation) is considered one pulse when both steps are used together. Atypical head space control operation may comprise from one to eightpulses. Typically, there could be two, three, four, or five pulses. Eachpulse could last from about one tenth of one second to five seconds orfrom five to fifteen seconds when conducted by automated high-speedequipment custom designed for this specific purpose. In someembodiments, the pulse may last from about 0.1 to about 2.0 seconds. Insome embodiments, the pulse may last from about 0.1 to about 1.0seconds, or from about 0.1 to about 0.4 seconds. When done using manualmethods, each pulse could take up to 30-60 seconds or longer. Such amanual process is described in more detail in Examples 1 and 4.Alternatively, a more automated process that was developed by thecurrent inventors is described in Example 5.

In certain embodiments, the compositions are part of a total parenteralnutrition regimen. The L-cysteine compositions described herein can beadmixed with amino acid solutions, such as crystalline amino acidinjection, for example, commercially available TRAVASOL® and TRAVASOLE®.

In certain aspects, the subject matter described herein is directed to asafe, stable composition from about 100 mL to about 1000 mL foradministration via a parenteral infusion within about 24 to about 48hours of admixture, comprising a mixture of a composition of L-Cysteinedescribed herein; and an amino acid composition that is essentially freeof L-Cysteine comprising one or more amino acids selected from the groupconsisting of: leucine, isoleucine, lysine, valine, phenylalanine,histidine, threonine, methionine, tryptophan, alanine, arginine,glycine, proline, serine, and tyrosine.

In certain embodiments, the subject matter described herein is directedto a stable TPN composition for infusion, comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof;

Aluminum in an amount from about 10 parts per billion (ppb) to about 80ppb;

cystine in an amount from about 0.001 wt % to about 2.0 wt % relative toL-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

one or more amino acids selected from the group consisting of: leucine,isoleucine, lysine, valine, phenylalanine, histidine, threonine,methionine, tryptophan, alanine, arginine, glycine, proline, serine, andtyrosine;

a pharmaceutically acceptable carrier, comprising water,

wherein, the amounts are from about 100 mL to about 1,000 mL and thetotal aluminum delivered by the said composition does not exceed about4-5 mcg/kg/day. In certain embodiments, the amounts include 150 mL, 200mL, 250 mL, 300 mL, 350 mL, 400 mL, 450 mL, 500 mL, 550 mL, 600 mL, 650mL, 700 mL, 750 mL, 800 mL, 850 mL, 900 mL and 950 mL.

In certain embodiments, the stable composition for infusion comprisesone or more amino acids selected from the group consisting of leucine,isoleucine, lysine, valine, phenylalanine, histidine, threonine,methionine, tryptophan, alanine, arginine, glycine, proline, serine, andtyrosine. In certain embodiments, the composition includes all of these.In certain embodiments, 500 mg of L-Cysteine is admixed with 12.5 gramof crystalline amino acid injection, such as that present in 250 mL of5% crystalline amino acid injection. In some aspects, 15 mg ofL-Cysteine is admixed with one gram of amino acids. In some otheraspect, 40 mg of L-Cysteine is admixed with one gram of amino acids.Depending on the needs of the subject, based on specific characteristicssuch as age, weight, and physiological factors such as renal function,the dose may be adjusted at or within these ranges of 15-40 mg ofL-Cysteine per gram of amino acids. See, for example, Tables 1-2 above.Thus, the pharmaceutical compositions comprising L-Cysteine can beformulated, dosed and administered in a fashion, i.e., amounts,concentrations, schedules, course, and vehicles, consistent with goodmedical practice. The “therapeutically and nutritionally effectiveamount” of the compound to be administered will be governed by suchconsiderations.

In certain embodiments, the compositions are essentially free ofsupplementary antioxidant. As used herein, this refers to the absence ofany substance that is added to the compositions specifically as anantioxidant. Naturally occurring antioxidants may still be present.

In certain embodiments, the compositions that comprise one or more ofthe above amino acids are essentially free of dextrose. However, incertain embodiments, the compositions that comprise one or more of theabove amino acids further comprise a sugar.

In certain embodiments, the pH of the compositions is about 1.0 to about2.5, or about 1.6 to about 2.0, or about 1.6, or about 1.7, or about1.8, or about 1.9 or about 2.0. For administration, the pH is generallyadjusted by admixing with other components to a pH of about 6.0 to about8.0, but generally around 7.0. In certain embodiments, the compositionsare essentially free of a buffer. In certain embodiments, thecompositions further comprise a buffer.

In particular embodiments, the subject matter described herein isdirected to a stable L-cysteine composition for injection that can beuseful for treatment of a variety of conditions, such as those describedabove. In further detail, L-cysteine can be administered in a variety offorms, such as the free base, L-cysteine hydrochloride, apharmaceutically acceptable salt thereof (e.g. sodium salt, calciumsalt, etc.), a hydrate thereof, the like, or a combination thereof. Insome specific examples, L-cysteine can be included in the L-cysteinecomposition for injection as L-cysteine hydrochloride monohydrate.

In particular embodiments, the subject matter described herein isdirected to a stable L-cysteine composition for injection, comprising:

about 34.5 mg/mL of L-cysteine free base, or a pharmaceuticallyacceptable salt thereof and/or hydrate thereof;

Aluminum in an amount of 130 ppb or below;

water;

wherein the composition is enclosed in a single-use container having avolume of from 10 mL to 100 mL, and is stable for 9 months or less.

In certain embodiments, the stable, safe L-cysteine composition canconsist essentially of L-cysteine, water, Aluminum in an amount of lessthan 200 ppb, cystine in an amount from about 0.001 wt % to about 2 wt %relative to L-cysteine, pyruvic acid in an amount from about 0.001 wt %to about 2 wt % to L-cysteine, headspace oxygen that is less than 4.0%and dissolved oxygen from about 0.1 ppm to about 1 ppm. Other tracecomponents or excipients do not materially affect the basic and novelcharacteristics of composition unless otherwise indicated, for example,undesirable anions and heavy metals.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. The container may also include a tamper-proofassemblage to prevent indiscreet access to the contents of the package.In addition, the container has deposited thereon a label that describesthe contents of the container. The label may also include appropriatewarnings, more specifically about the Aluminum content of the L-Cysteinecomposition. For example, the label may indicate that the Aluminum inthe container may be at 100 ppb or 100 mcg/L. In another embodiment, thelabel may indicate that the Aluminum in the container may be at 120 ppbor 120 mcg/L. In some specific embodiments, the Aluminum level may bedescribed as not more than 120 ppb, or not more than 120 mcg/L, or NMT120 ppb, or NMT 120 mcg/L. In addition to the label, the labelingassociated with the L-Cysteine product may have the same description ofAluminum.

It should be understood that, as is customary in the pharmaceuticalarts, the phrases “NMT” or “not more than” represents the upper limit,but also is understood not to mean that the value is zero or even can bezero. For example, a statement that the Aluminum levels are NMT 120 ppbis not understood by the practitioners in the art that the Aluminumlevels are at zero ppb in that particular vial bearing that label.Pharmacists and other health care professionals instead would interpretfor purposes of calculating the Aluminum content of a TPN preparationusing that specific L-Cysteine vial that the Aluminum levels are at 120ppb so that, even if the actual amount is lower than the 120 ppb in theproduct, they err on the conservative side. This is the custom in thepharmaceutical industry developed and practiced to safeguard the healthof patients. If indeed the label is intended to convey with certaintythat the actual Aluminum level is zero ppb, the label then would statethat fact or indicate that the product is free of Aluminum.

Similarly, any numerical value expressed as “less than” is intended toconvey that the value is below that certain numerical value, including,as the case may be zero. For example, when it is stated herein thatAluminum levels are less than about 20 ppb, it is understood that insome embodiments the Aluminum can be, but not necessarily in all cases,anywhere from zero to about 19 ppb. It is also understood that this may,but not necessarily in all cases, encompass those situations where thelevels are below quantitation limit, but the presence of Aluminum isdetectable. In those cases where the Aluminum (or any other measuredmaterial generally) where the material is detectable but is below thelevel of quantitation, that numerical value can be considered forexample as being about 1.0 (for Aluminum) or 0.001 (for Cystine orPyruvic acid), or 1.0 ppb (for elements) or 1.0 ppm (for iodide orfluoride). Unless an actual analysis is made of the product and aspecific number is determined, there is no certainty of the actualvalue. The US FDA does not require this precision in the labeling on aproduct-by-product or even batch-by-batch because that is impracticablein a commercial supply chain setting for drug products.

Thus, the phrases “NMT” or “not more than” or “less than” are terms ofart in the pharmaceutical industry. Those in the industry do not assumethese terms necessarily represent zero in all cases, even though that isa possibility. When calculating the Aluminum amounts for purposes ofpreparing parenteral nutrition products the artisan never assumes theAluminum levels are zero in order to safeguard the patient health.Accordingly, this present disclosure and the claims derived therefromare to be read and understood in light of this custom and practice inthe art.

As mentioned above, the L-cysteine compositions for infusion mayoptionally be mixed with pharmaceutically acceptable excipients, alsodescribed in Remington's Pharmaceutical Sciences (1980) 16^(th) edition,Osol, A. Ed., Mack Publishing Co., Easton, Pa.

As noted above, the diluted L-cysteine composition for infusion cantypically have a pH of from about 5.0 to about 8.0, or from about 6.0 toabout 7.0. However, dilution and administration of the L-cysteinecomposition for infusion will typically be overseen by a licensedmedical professional, who may recommend a pH outside of the rangesrecited herein under certain circumstances. Additionally, the dilutedL-cysteine composition for infusion can typically have a tonicity offrom about 250 milliosmoles/liter (mOsmol/L) to about 1,000 mOsmol/L, ormore, or of from about 350 mOsmol/L to about 475 mOsmol/L. However,dilution and administration of the L-cysteine composition for infusionwill typically be overseen by a licensed medical professional, who mayrecommend a tonicity outside of the ranges recited herein under certaincircumstances.

III. Methods

The subject matter described herein is directed to methods of treating asubject having an adverse health condition that is responsive toL-cysteine administration. The methods can include diluting the stableL-cysteine composition described herein with an intravenous fluid toprepare a diluted L-cysteine composition for infusion. The methods canfurther include parenterally administering the diluted L-cysteinecomposition to provide a therapeutically effective dose of L-cysteine ora pharmaceutically acceptable salt thereof and/or hydrate thereof to thesubject in a therapeutically effective dosing regimen.

In certain embodiments, the subject matter described herein is directedto a method of reducing Aluminum administration from a total parenteralnutrition regimen comprising L-cysteine, the method comprising, mixing acomposition comprising L-cysteine or a pharmaceutically acceptable saltthereof and/or hydrate thereof comprising:

Aluminum in an amount from about 1.0 parts per billion (ppb) to about250 ppb or from about 10 ppb to about 80 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine; and

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

with a composition comprising one or more amino acids selected from thegroup consisting of: leucine, isoleucine, lysine, valine, phenylalanine,histidine, threonine, methionine, tryptophan, alanine, arginine,glycine, proline, serine, and tyrosine; and

a pharmaceutically acceptable carrier, comprising water, to form acomposition for infusion of about 100 mL to about 1000 mL,

wherein the Aluminum provided in said parenteral nutrition regimen isfrom about 1-2 to about 4-5 micrograms/kg/day.

In certain aspects, the compositions and methods described herein aredirected to methods of administering L-Cysteine together with acomposition for parenteral nutrition, comprising:

diluting a stable L-cysteine composition for injection as describedherein with a parenteral nutrition composition to form a mixture; and

parenterally administering the mixture to a subject in need thereof in atherapeutically and/or nutritionally effective dose. In one aspect, thesubject is a neonatal weighing less than 2 kilos. In another aspect, thesubject is a pediatric patient that is from about 0.2 kilos to about 20kilos. In another aspect, the subject is an adult requiring parenteralnutrition.

In certain embodiments, the subject matter described herein is directedto a method of reducing Aluminum administration from a parenteralnutrition regimen comprising L-cysteine, comprising:

administering to a subject a composition comprising L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof;

Aluminum in an amount from about 10.0 parts per billion (ppb) to about250 ppb, or from about 10 ppb to about 80 ppb;

cystine in an amount from about 0.01 wt % to about 2.0 wt % relative toL-cysteine;

pyruvic acid in an amount from about 0.01 wt % to about 2.0 wt %relative to L-cysteine;

one or more amino acids selected from the group consisting of: leucine,isoleucine, lysine, valine, phenylalanine, histidine, threonine,methionine, tryptophan, alanine, arginine, glycine, proline, serine, andtyrosine,

a pharmaceutically acceptable carrier, comprising water,

wherein, the amounts are about 100 mL to about 1,000 mL,

wherein the Aluminum administered to said subject is reduced compared toadministration of a standard parenteral composition comprisingL-cysteine and Aluminum at a range of from about 900 ppb to about 5,000ppb.

In certain embodiments, the methods provide that the reduction in theamount of Aluminum administered is relative to the amount of Aluminum ina L-cysteine injection composition having more than 500 ppb Aluminum, ormore than 250 ppb Aluminum. The relative reduction in Aluminum can be upto 90%, up to 80%, up to 70%, up to 60%, up to 50%, up to 40%, up to30%, up to 20%, up to 10%, or up to 5%, as compared to the amount ofAluminum administered with a L-cysteine composition having more than 500ppb Aluminum, or more than 250 ppb Aluminum. In certain embodiments, thereduction occurs over the span of a day, a week, a month or the durationof the TPN regimen.

In certain aspects, the subject matter described herein is directed tomethods of treating a subject having an adverse health condition that isresponsive to L-cysteine administration, comprising:

diluting a stable L-cysteine composition as described herein with anintravenous fluid to prepare a diluted L-cysteine composition forinfusion; and

infusing the diluted L-cysteine composition for infusion to a subject toprovide a therapeutically effective dose of L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof to thesubject in a therapeutically effective dosing regimen.

In certain embodiments, the method of treating a subject having anadverse health condition that is responsive to L-cysteine administrationfurther comprises, before the diluting step, admixing the stableL-cysteine composition with an amino acid solution, such as, crystallineamino acid injection. In this aspect, the methods comprise diluting withan intravenous fluid the stable L-cysteine composition admixed with anamino acid solution, wherein the fluid comprises dextrose.

In certain embodiments, the adverse health condition is the lack of anecessary enzyme in the trans-sulfuration pathway that convertsmethionine to L-cysteine. Other adverse health conditions includeinadequate absorption resulting from short bowel syndrome;gastrointestinal fistula; bowel obstruction; prolonged bowel rest;severe malnutrition; significant weight loss and/or hypoproteinaemiawhen enteral therapy is not possible; other disease states or conditionsin which oral or enteral feeding are not an option.

For most preterm infants, the administration should be considered as ashort-term bridge to provide nutritional support until full enteralnutrition can be provided. Such instances include: Immediately afterbirth, to provide essential nutrition as enteral feeds are commenced andadvanced, and/or during periods of acute gastrointestinal malfunction(eg, due to septic ileus or necrotizing enterocolitis).

In certain embodiments, the administering is a single daily dose, ormultiple daily doses, or is administered in accordance with a TPNregimen, for example, the dosing can be over a day, several days, a weekor several weeks, a month or several months.

In certain embodiments, the subject is an infant or pre-term infant fromnewborn until about 6 months of age. As presented in Tables 1 and 2above, the subjects can be from a pre-term infant to an adult that is inneed of L-Cysteine supplementation. Thus, the subject can be a subject“in need of” the methods of described herein, for example, in need ofthe therapeutic effects or prophylactic benefits of the methods. Incertain embodiments, the subject is a subject in need of a totalparenteral nutrition (TPN) regimen.

In certain embodiments, the intravenous fluid is selected from the groupconsisting of isotonic saline, glucose solution, glucose saline,dextrose solution, crystalline amino acid solution, lipids, andcombinations thereof.

In certain embodiments, the L-cysteine is L-cysteine hydrochloridemonohydrate.

In certain embodiments, the diluted L-cysteine composition for infusionis typically administered via intravenous infusion. The selection ofadministration rate and site of infusion (i.e., via a peripheral orcentral vein) are within the ordinary skill in the art of medicine,pharmaceutical, nursing, and nutritional sciences.

The diluted L-cysteine composition for infusion can be administereduntil a therapeutically effective dose is achieved. In some examples, atherapeutically effective dose of L-cysteine or a pharmaceuticallyacceptable salt thereof and/or hydrate thereof can be from about 0.01 mgto about 2.0 mg L-cysteine. Again, therapeutically effective doses candepend on whether the patient is a pediatric patient or an adultpatient. For example, for preterm or term infants less than 1 month ofage, the therapeutically effective dose is about 45 to 60 mcg/kg/day.For pediatric patients 1 month to less than 1 year of age, thetherapeutically effective dose is 30 to 45 mcg/kg/day. For pediatricpatients 1 year to 11 years of age, the therapeutically effective doseis about 15 to 30 mcg/kg/day. For pediatric patients 12 years to 17years of age, the therapeutically effective dose is about 4 to 7.5mcg/kg/day. For adults, i.e., stable patients, the therapeuticallyeffective dose is 4 to 5 mcg/kg/day. For adults that are critically ill,the therapeutically effective dose is 7.5 to 10 mcg/kg/day.

The number of doses given daily can vary as desired or needed per thetherapeutically effective dosing regimen. In some examples, thetherapeutically effective dosing regimen can include dailyadministration of the diluted L-cysteine composition. In other examples,the therapeutically effective dosing regimen can include twice-dailyadministration of the diluted L-cysteine composition. In some furtherexamples, the therapeutically effective dosing regimen can provide lessthan or equal to 5 μg/kg/d of Aluminum. In still further examples, thetherapeutically effective dosing regimen can provide less than or equalto 4 μg/kg/d of Aluminum, or less than or equal to 3 μg/kg/d ofAluminum. In certain embodiments, the methods result in a daily dosageof Aluminum from the composition of from about 2 μg/kg/d to not morethan 5 μg/kg/d.

The diluted L-cysteine composition for infusion can be administered forthe treatment of a number of conditions. For example, L-cysteine can beadministered to meet the intravenous amino acid nutritional requirementsof individuals (e.g. infants) receiving total parenteral nutrition. Assuch, in some examples, the subject can be a subject in need of totalparenteral nutrition (TPN). In some additional examples, L-cysteine canbe administered for the treatment of osteoarthritis, rheumatoidarthritis, angina, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), influenza, acute respiratory distress syndrome (ARDS),diabetes (e.g. type 2 diabetes), the like, or a combination thereof.

In certain embodiments, the subject matter described herein is directedto methods of preparing a composition, comprising:

Stirring Water for Injection, USP (WFI) in a vessel at a temperature ofNMT about 60° C.;

Contacting the stirring WFI with Argon until the dissolved oxygen is NMT1 ppm;

Allowing the vessel to cool to a temperature of NMT 30° C.;

Contacting under the Argon the WFI with L-Cysteine Hydrochloride,Monohydrate, USP (L-Cysteine) for NLT about 15 mins;

Continuing the mixing under Argon until the dissolved oxygen is NMT 1ppm;

Adjusting the pH to about 1.8 with concentrated Hydrochloric Acid, NFand/or 5.0 N Sodium Hydroxide, NF;

Mixing for a minimum of about 10 minutes;

Capping the vessel under Argon and allowing to stand;

Filling said mixed liquid into individual single use containers;

Reducing head space oxygen to about 5.0% to 0.5% and sealing saidcontainers wherein the dissolved oxygen in the container is about 0.1ppm to about 5 ppm.

The subject matter described herein includes, but is not limited to, thefollowing specific embodiments:

1. A stable L-cysteine composition for parenteral administration,comprising:

L-cysteine or a pharmaceutically acceptable salt thereof and/or hydratethereof in an amount from about 10 mg/mL to about 100 mg/mL;

Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) toabout 250 ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine;

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

a pharmaceutically acceptable carrier, comprising water;

headspace O₂ that is from about 0.5% to 4.0% from the time ofmanufacture to about 1 month from manufacture when stored at roomtemperature;

dissolved oxygen present in the carrier in an amount from about 0.1parts per million (ppm) to about 5 ppm from the time of manufacture toabout 1 month from manufacture when stored at room temperature,

wherein the composition is enclosed in a single-use container having avolume of from about 10 mL to about 100 mL.

2. The composition of embodiment 1, wherein the composition isessentially free of an antioxidant.

3. The composition of embodiment 1 or 2, wherein said Aluminum ispresent in an amount from about 1.0 ppb to about 200 ppb.

4. The composition of embodiment 1, 2 or 3, wherein said Aluminum ispresent in an amount from about 1.0 ppb to about 180 ppb.

5. The composition of embodiment 1, 2, 3 or 4, wherein said Aluminum ispresent in an amount from about 1.0 ppb to about 170 ppb.

6. The composition of embodiment 1, 2, 3, or 5, wherein said Aluminum ispresent in an amount from about 1.0 ppb to about 160 ppb.

7. The composition of embodiment 1, 2, 3, 4, 5 or 6, wherein saidAluminum is present in an amount from about 1.0 ppb to about 150 ppb.

8. The composition of embodiment 1, 2, 3, 4, 5, 6 or 7, wherein saidAluminum is present in an amount from about 1.0 ppb to about 130 ppb.

9. The composition of embodiment 1, 2, 3, 4, 5, 6, 7 or 8, wherein saidAluminum is present in an amount from about 1.0 ppb to about 100 ppb.

10. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,wherein said Aluminum is present in an amount from about 1.0 ppb toabout 50 ppb.

11. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11,wherein said Aluminum is present in an amount from about 1.0 ppb toabout 20 ppb or from about 1.0 ppb to about 10 ppb.

12. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11,further comprising one or more heavy metals selected from the groupconsisting of Lead (in an amount of from about 1 ppb to about 10 ppb),Nickel (in an amount of from about 5 ppb to about 40 ppb), Arsenic (inan amount of from about 0.1 ppb to about 10 ppb), and Mercury (in anamount of from about 0.2 ppb to about 5.0 ppb).13. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or12, wherein said heavy metals are present in total in an amount fromabout 2.0 ppb to about 8.0 ppb.14. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12or 13, further comprising iodide and fluoride, each present in an amountfrom about 0.1 ppm to about 20 ppm.15. The composition of embodiment 14, wherein said ions are present intotal an amount from about 2.8 ppm to about 5.8 ppm.16. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14 or 15, wherein said dissolved oxygen is present in an amount fromabout 0.1 ppm to about 5 ppm.17. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15 or 16, wherein said dissolved oxygen is present in an amountfrom about 0.1 ppm to about 3 ppm.18. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16 or 17, wherein said dissolved oxygen is present in anamount from about 0.10 ppm to about 2.0 ppm.19. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17 or 18, wherein said dissolved oxygen is present in anamount from about 0.1 ppm to about 1.0 ppm.20. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18 or 19, wherein the composition has been stored atroom temperature.21. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19 or 20, wherein the storage is for 1 year orless.22. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the storage is for about 9months.23. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof ispresent in the composition in an amount from about 20 mg/mL to about 70mg/mL.24. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof ispresent in the composition in an amount of about 50 mg/mL.25. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, wherein the containeris an internally coated glass container.26. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, wherein saidinternally coated glass container is coated with SiO2.27. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, essentiallyfree of cystine precipitate.28. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, whereinsaid L-cysteine is present in an amount of about 37.5 mg/mL as freebase, or a pharmaceutically acceptable salt thereof and/or hydratethereof.29. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein the Aluminum is present in the composition in an amount not morethan 200 ppb after storage at ambient temperature for a period of 3months or less, said Aluminum comprising, from about 1.0 ppb to about100 ppb of Aluminum from the container, from about 1.0 ppb to about 100ppb of Aluminum from stopper for the container, from about 1.0 ppb toabout 100 ppm of Aluminum from the L-cysteine, and from about 1.0 ppb toabout 20 ppb of Aluminum from the water.30. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein the Aluminum is present in the composition in an amount not morethan 200 ppb after storage at ambient temperature for a period of 6months or less, said Aluminum comprising, from about 0 ppb to about 100ppb of Aluminum from the container, from about 1.0 ppb to about 100 ppbof Aluminum from stopper for the container, from about 1.0 ppb to about100 ppm of Aluminum from the L-cysteine, and from about 0 ppb to about20 ppb of Aluminum from the water.31. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein the Aluminum is present in the composition in an amount not morethan 200 ppb after storage at ambient temperature for a period of 9months or less, said Aluminum comprising, from about 1.0 ppb to about100 ppb of Aluminum from the container, from about 1.0 ppb to about 100ppb of Aluminum from stopper for the container, from about 1.0 ppb toabout 100 ppm of Aluminum from the L-cysteine, and from about 1.0 ppb toabout 20 ppb of Aluminum from the water.32. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein the Aluminum is present in the composition in an amount not morethan 200 ppb after storage at ambient temperature for a period of 12months or less, said Aluminum comprising, from about 1.0 ppb to about100 ppb of Aluminum from the container, from about 1.0 ppb to about 100ppb of Aluminum from stopper for the container, from about 1.0 ppb toabout 100 ppm of Aluminum from the L-cysteine, and from about 1.0 ppb toabout 20 ppb of Aluminum from the water.33. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein cystine is present in the composition in an amount not more than2 wt % relative to L-cysteine after storage at ambient temperature for aperiod of 9 months or less.34. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein cystine is present in the composition in an amount not more than1 wt % relative to L-cysteine after storage at ambient temperature for aperiod of 9 months or less.35. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein cystine is present in the composition in an amount not more than0.5 wt % relative to L-cysteine after storage at ambient temperature fora period of 9 months or less.36. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein cystine is present in the composition in an amount of about 0.3wt % relative to L-cysteine after storage at ambient temperature for aperiod of 9 about months.37. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 2 wt % relative to L-cysteine after storage at ambient temperaturefor a period of 9 months or less.38. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 1 wt % relative to L-cysteine after storage at ambient temperaturefor a period of 9 months or less.39. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 0.5 wt % relative to L-cysteine after storage at ambienttemperature for a period of 9 months or less.40. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 0.3 wt % relative to L-cysteine after storage at ambienttemperature for a period of 9 months or less.41. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 0.2 wt % relative to L-cysteine after storage at ambienttemperature for a period of 9 months or less.42. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein pyruvic acid is present in the composition in an amount not morethan 0.1 wt % relative to L-cysteine after storage at ambienttemperature for a period of 9 months or less.43. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 1.0%.44. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 0.9%.45. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 0.8%.46. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 0.6%.47. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 0.4%.48. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,further comprising in the vial, headspace oxygen in an amount of lessthan 0.2%.49. The composition of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28,wherein the pH of the composition is about 1.6 to about 2.0.50. A stable composition from about 100 mL to about 1000 mL foradministration via a parenteral infusion within about 24 to about 48hours of admixture, comprising a mixture of a composition of L-Cysteineof embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49; and anamino acid composition that is essentially free of L-Cysteine comprisingone or more amino acids selected from the group consisting of: leucine,isoleucine, lysine, valine, phenylalanine, histidine, threonine,methionine, tryptophan, alanine, arginine, glycine, proline, serine, andtyrosine.51. The stable composition for infusion of embodiment 50, wherein thecomposition of L-Cysteine is the composition of embodiment 1, 12 or 28.52. The stable composition for injection of embodiment 50 or 51, whereinthe Aluminum is present in an amount from about 1.0 parts per billion(ppb) to about 100 ppb.53. The stable composition for injection of embodiment 50, 51 or 52,wherein the Aluminum is present in an amount from about 1.0 parts perbillion (ppb) to about 50.0 ppb.54. The stable composition for injection of embodiment 50, 51, 52 or 53,wherein the Aluminum is present in an amount from about 1.0 parts perbillion (ppb) to about 30.0 ppb.55. The stable composition for injection of embodiment 50, 51, 52, 53 or54, further comprising a sugar.56. The stable composition for injection of embodiment 50, 51, 52, 53,54 or 55, wherein the sugar is dextrose.57. A method of reducing Aluminum administration from a parenteralnutrition regimen comprising L-cysteine, comprising:

-   -   administering to a subject a composition of embodiment 50, 51,        52, 53, 54, 55 or 56,

wherein the Aluminum administered to said subject is reduced compared toadministration of a standard parenteral composition comprisingL-cysteine.

58. The method of embodiment 57, wherein the Aluminum is reduced byabout 5%, or about 10%, or about 15%, or about 20%, or about 25%, orabout 30%, or about 35%, or about 40%, or about 45%, or about 50%, orabout 55%, or about 60%, or about 65%, or about 70%, or about 75%, orabout 80%, or about 85%, or about 90%, or about 95%.59. A method of reducing Aluminum administration from a total parenteralnutrition regimen comprising L-cysteine, the method comprising, mixing acomposition comprising L-cysteine or a pharmaceutically acceptable saltthereof and/or hydrate thereof comprising:

Aluminum in an amount from about 10 parts per billion (ppb) to about 80ppb;

L-cystine in an amount from about 0.001 wt % to about 2.0 wt % relativeto L-cysteine; and

pyruvic acid in an amount from about 0.001 wt % to about 2.0 wt %relative to L-cysteine;

with a composition comprising one or more amino acids selected from thegroup consisting of: leucine, isoleucine, lysine, valine, phenylalanine,histidine, threonine, methionine, tryptophan, alanine, arginine,glycine, proline, serine, and tyrosine; and

a pharmaceutically acceptable carrier, comprising water,

to form a composition for infusion having a volume of about 100 mL toabout 1000 mL, wherein the Aluminum provided in said parenteralnutrition regimen is from about 1-2 to about 4-5 micrograms/kg/day.

60. A method of treating a subject having an adverse health conditionthat is responsive to L-cysteine administration, comprising:

diluting a stable L-cysteine composition of embodiments 50, 51, 52, 53,54, 55 or 56, with an intravenous fluid to prepare a diluted L-cysteinecomposition for infusion; and

infusing the diluted L-cysteine composition for infusion to a subject toprovide a therapeutically effective dose of L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof to thesubject in a therapeutically effective dosing regimen.

61. The method of embodiment 57, 58, 59, or 61, wherein saidadministering is from 30 minutes to about 24-48 hrs.

62. The method of embodiment 61, wherein the amount of Aluminum in thecomposition results in a daily dosage of Aluminum from about 1mcg/kg/day to about 4 mcg/kg/day, or about 2 mcg/kg/day to about 4mcg/kg/day, or about 1 mcg/kg/day to about 5 mcg/kg/day, or about 2mcg/kg/day to about 5 mcg/kg/day.63. The method of embodiment 61 or 62, wherein the intravenous fluid isa member selected from the group consisting of: isotonic saline, glucosesolution, glucose saline, dextrose solution, crystalline amino acidsolution, and combinations thereof.64. The method of embodiment 61, 62 or 63, wherein administering isperformed via intravenous infusion.65. The method of embodiment 61, 62, 63, or 64, wherein L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof isadministered at a rate of from about 1 mL/min to about 10 ml/min.66. The method of embodiment 61, 62, 63, 64 or 65, wherein thetherapeutically effective dose of L-cysteine or a pharmaceuticallyacceptable salt thereof and/or hydrate thereof is an amount from about50 mg to about 1200 mg.67. The method of embodiment 61, 62, 63, 64, 65 or 66, wherein thetherapeutically effective dose of L-cysteine or a pharmaceuticallyacceptable salt thereof and/or hydrate thereof is an amount of about100-500 mg.68. The method of embodiment 61, 62, 63, 64, 65, 66 or 67, wherein theL-cysteine is L-cysteine hydrochloride monohydrate.69. The method of embodiment 61, 62, 63, 64, 65, 66, 67 or 68, whereinthe subject is a subject in need of total parenteral nutrition (TPN).70. The method of embodiment 61, 62, 63, 64, 65, 66, 67, 68 or 69,wherein the subject is an infant having an age of 6 months or less.71. The method of embodiment 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or71, wherein the therapeutically effective dosing regimen is a totalparenteral nutrition (TPN) dosing regimen.72. A method of preparing the composition of any above embodiment,comprising stirring Water for Injection, USP (WFI) in a vessel at atemperature of NMT about 60° C.;

Contacting the stirring WFI with Argon until the dissolved oxygen is NMT1 ppm;

Allowing the vessel to cool to a temperature of NMT 30° C.;

Contacting under the Argon the WFI with L-Cysteine Hydrochloride,Monohydrate, USP (L-Cysteine) for NTL about 15 mins;

Continuing the mixing under Argon until the dissolved oxygen is NMT 1ppm;

Adjusting the pH to about 1.8 with concentrated Hydrochloric Acid, NFand/or 5.0 N Sodium Hydroxide, NF;

Mixing for a minimum of about 10 minutes;

Capping the vessel under Argon and allowing to stand; and

Performing Head Space oxygen Reduction after filling, wherein thedissolved oxygen is about 0.1 ppm to about 5 ppm.

With this in mind, the following examples are intended to illustrate,but not limit, various aspects of the compositions and methods describedherein.

EXAMPLES Example 1 Compounding L-Cysteine Hydrochloride Injection, USP,50 mg/mL, 10 mL Vial

Compounding was initiated with the addition of 40±1.0 kg of Water forInjection, USP (WFI) was added to the Xcellerex Mixing System via anaddition funnel. A target water temperature of NMT 60° C. was maintainedthroughout WFI addition using a heat exchanger. With continuous mixingat a speed of 126 rpm, Argon overlaying of the WFI began in the mixingbag and continued until the dissolved oxygen was NMT 1 ppm; then themixing bag was allowed to cool to a temperature of NMT 30° C.

With continuous mixing and Argon overlaying, the L-CysteineHydrochloride, Monohydrate, USP (L-Cysteine) was added directly into thevortex of the mixing bag. The mixing continued for NLT 15 minutes oruntil complete dissolution was observed. The dissolved oxygen contentwas measured and recorded prior to the addition of L-Cysteine,immediately following the addition of L-Cysteine, and following the NLT15-minute mixing period. With continuous mixing and Argon overlaying,the temperature, pH and dissolved oxygen of the solution was measuredand recorded. Argon overlaying continues until the dissolved oxygen wasNMT 1 ppm.

With continuous mixing and Argon overlaying, the solution's pH wasadjusted to a target of 1.8 with concentrated Hydrochloric Acid, NFand/or 5.0 N Sodium Hydroxide, NF. Following pH adjustment, the solutionwas allowed to mix for a minimum of 10 minutes, and then the pH wasverified and adjusted as needed with the Hydrochloric Acid, NF and/or NSodium Hydroxide, NF. Then, the solution's weight, adjusted pH anddissolved oxygen was measured and recorded.

With continuous mixing and Argon overlaying, the solution was q.s.'dwith the WFI to a final weight of 50.6 kg and allowed to mix forapproximately 10 minutes. The final solution weight, solutiontemperature, solution pH, and dissolved oxygen was then measured andrecorded. Following these steps, the mixing bag was fully inflated withArgon and capped, and the solution was transferred from the mixing bagto the solution holding bag.

Example 2 L-Cysteine Injection in High Quality Glass Vials

L-Cysteine injection was compounded as per Example 1. The bulk solutionwas filled then using high quality glass vials (10 mL) from Schott.These vials are known as Schott Type 1 USP glass. The glass was astandard glass of pharmaceutical quality but was uncoated. The productwas put on stability and was monitored for impurities, particulates, andAluminum. The product was quite stable for all the time points tested upto 12 months. There were no unacceptable particulate counts.

However, as the data show, the product resulted in an unacceptably highaluminum content. The data for aluminum levels are shown below.

TABLE 6 Aluminum Levels 6 Months Lot # Release 25° C./60% RH 40° C./75%RH XMHH1609 212 ppb 569 ppb 1.306 ppb XMHH1610 199 ppb 748 ppb 1,374 ppbXMHH1611 230 ppb 726 ppb 1,044 ppb

Example 3 L-Cysteine Injection in Plastic Vials

L-Cysteine injection was compounded as per Example 1. The bulk solutionwas filled then using plastic vials obtained from Medicopak, Inc. Thesevials are made of cyclic olefin copolymer (COC). The product was put onstability and was monitored for impurities, particulates, and Aluminum.The product was not stable beyond 1 month at accelerated storageconditions and failed at room temperature conditions by the third monthdata point.

TABLE 7 Particulate levels 1 Month/ 3 Month/ Lot Number/Vial Release 40°C./75% RH* 25° C./60% RH* XMHG1700/10 mL COC Passing Failed Visual,Failed Visual, vial particulates particulates XMHG1701/10 mL COC PassingFailed Visual, Failed Visual, vial particulates particulates XMHG1702/10mL COC Passing Failed Visual, Failed Visual, vial particulatesparticulatesHowever, the product showed acceptable aluminum content. The data foraluminum levels are shown below.

TABLE 8 Aluminum Levels Time Point Lot XMHG 1700 Lot XMHG 1701 Lot XMHG1702 Time Zero 1 ppb 2 ppb 1 ppbAluminum at additional time points was not measured because the productwas abandoned due to unacceptably high particulate count.

Example 4 Headspace Reduction and Argon Overlay

Data from Example 3 show that plastic vials do not provide the desiredpurity and stability of a L-cysteine composition for injection. Thisstudy was to evaluate the parameters to determine headspace oxygenreduction conditions. The product was manufactured as per Example 1. Thedrug product was overlaid with Argon until the dissolved oxygen levelswere no more than (NMT) 1 part per million (PPM). Vials were filled andplaced in the VirTis Benchmark Lyophilizer, OP4159, for Head Spacereduction. In addition, empty vials were also placed into the lyo forHead Space reduction as part of the study.

Multiple points were monitored during the manufacturing process as partof the study including the following: 1) Compounding; 2) Pre-Filling; 3)Filling; 4) Post Filling; and 5) Head Space Reduction (HSR). Themonitoring involved taking dissolved oxygen (DO) measurements on drugproduct for filled vials throughout the manufacturing process andperforming Head Space Gas Analysis on drug product for both filled andempty vials post head space reduction. Additionally, fill hold samplesrepresenting the maximum exposure during the filling step were analyzedfor the dissolved oxygen and Head Space Oxygen Analysis.

The sampling and testing that was performed per the study is shown inTable 9. Samples were collected throughout the manufacturing process todetermine the impact of critical process parameters on its predeterminedcritical quality attribute.

TABLE 9 Sampling and Testing Methodology Sample Testing AcceptanceOperation Location/Quantity Requirements Criteria Com- The bulk solutionwas mixed under Dissolved Dissolved pounding Argon overlaying. Measureand record Oxygen Oxygen <1 ppm final solution weight, solutiontemperature, solution pH, and dissolved oxygen. Measure and record thefinal dissolved oxygen. Filling For Load A [Trays 1-4, 17-20] useDissolved Dissolved forceps to remove four (4) filled vials OxygenOxygen = from each tray as it is filled Fully seat Report Value thestoppers of the removed filled vials immediately after removal and thenlabel vials appropriately Filling As Tray 1 is loaded into the Lyo,using Dissolved Dissolved Hold forceps, carefully remove 20 vials fromOxygen Oxygen = the appropriate locations. Do not fully Report Valuestopper the vials. Mark the vials “Fill Hold” Similarly, after Tray 21has been completely filled and is being placed into the cart, useforceps to remove twenty (20) filled vials from the appropriate As Tray21 is being loaded into the Lyophilizer for Head Space Reduction, useforceps to remove two (2) of the vials marked “Fill Hold”, fully seatthe stoppers of the vials, and label appropriately. Lyo For Trays 1-4,17-20, 21-24, and Dissolved Dissolved Loading 37-40, use forceps toremove two (2) Oxygen Oxygen = filled vials, as each tray is loaded intoReport Value the Lyo, fully seat the stoppers of the vials, and labelappropriately Capping Following headspace reduction and DissolvedDissolved immediately prior to loading each tray Oxygen Oxygen = intothe RAB for capping, use forceps to Head Space Report Value remove four(4) filled vials from each Gas Analysis Head Space Gas tray. Place amark on each of the Analysis = removed vials for identification ReportValue purposes and place the marked vials back into the tray. Load thetray into the RAB for capping. Following the capping of each tray,remove the marked vials from the tray and label appropriately. CappingFollowing headspace reduction and Dissolved Dissolved Fill Hold capping,remove the eighteen (18) vials Oxygen Oxygen = marked “Fill Hold” fromTray 21 for Head Space Report Value testing. Gas Analysis Head Space GasAnalysis = Report Value

The data collected are as follows: Dissolved oxygen; Comparison ofdissolved oxygen levels per tray at various stages of the manufacturingprocess; Filled vials head space oxygen; Held vials dissolved oxygen(ppm) and head space oxygen content (%); Comparison of Post Head SpaceDissolved Oxygen (ppm) and Head Space Oxygen Content (%).

Dissolved oxygen data at various stages of the manufacturing process areshown in Table 10. A two (2) hour delay in the DO testing for the PostFilling—Pre HSR samples (Tray 1-4; tested using gas calibration)exhibited an average value of 11.77 ppm, an increase of 6.65 ppm fromthe average of 5.12 ppm measured live time after filling using theliquid calibration. Furthermore, the samples tested live time but usingthe gas calibration (Tray 17-20) exhibited an average value of 6.41 ppm,an increase of 1.29 ppm from the average of 5.12 ppm measured afterfilling using the liquid calibration. Starting Tray 21 of the PostFilling-Pre HSR step, the calibration was corrected to a liquidcalibration. Comparison of dissolved oxygen levels at various stages ofthe manufacturing process is provided in FIGS. 1 and 2.

TABLE 10 Dissolved Oxygen Levels. Tray Post Filling - Post Filling -During Post HSR - Capping - Number Pre HSR (ppm) Loading of Lyo (ppm)Filled Vials (ppm) 1 11.932 10.179 0.480 2 11.228 9.925 0.470 3 11.48610.577 0.508 4 12.441 10.370 0.409 17 6.808 9.893 0.525 18 6.628 9.8590.707 19 5.860 9.854 0.486 20 6.343 9.720 0.495 21 5.641 10.329 0.735 225.374 10.308 0.546 23 5.190 10.149 0.481 24 7.073 9.844 0.541 37 4.3289.544 0.403 38 3.604 9.251 0.378 39 4.559 9.265 0.390 40 5.173 9.5770.369 Average 5.117 9.915 0.495 STD 1.03 0.39 0.11 % RSD 20.1 3.9 21.3

TABLE 11 Filled Vials Head Space Oxygen. Tray Post HSR - Capping -Filled Vials Post Capping - Empty Vials Number (% Oxygen) (% Oxygen) 11.147 0.981 2 1.399 1.116 3 1.551 0.980 4 0.950 1.139 17 1.382 1.156 181.766 1.236 19 1.154 1.224 20 1.265 1.180 21 1.844 1.221 22 1.365 1.16923 0.890 1.295 24 1.148 1.114 37 0.880 1.300 38 0.871 1.151 39 0.8501.097 40 0.889 1.042 Average 1.209 1.150 STD 0.32 0.10 % RSD 26.7 8.3

TABLE 12 Held vials dissolved oxygen (ppm) and head space oxygen content(%). Held Dissolved Oxygen Dissolved Oxygen Head Space Oxygen Vials -Post Filling - Post HSR - % Post HSR - Tray 1/ Loading of Lyo Capping -Filled Capping - Filled Vials Tray 21 (ppm) Vials (ppm) (%) Sample 110.685 0.578 1.563 Sample 2 10.467 0.588 1.390 Sample 3 — 0.565 1.522Sample 4 — 0.550 1.447 Average 10.576 0.570 1.481 STD 0.15 0.02 0.08 %RSD 1.5 2.9 5.2

TABLE 13 Comparison of Post Head Space Dissolved Oxygen (ppm) and HeadSpace Oxygen Content (%). Dissolved Dissolved Head Space Oxygen OxygenOxygen % Pre HSR (ppm) Post HSR - (ppm) Post HSR (%) PROT-000055 Study —— 1.150 Empty Vials Avg. PROT-000055 Study 9.915 0.495 1.209 FilledVials Avg. 2018-RD-022 Study — — 0.49 Empty Vials Avg. 2018-RD-022 Study7.14 2.55 1.27 Filled Vials Avg. Lot XMHJ1705 — 0.637 2.28 Lot XMHJ1706— 0.391 1.92 Lot XMHJ1707 — 1.585 1.94

The results from these experiments demonstrate the effectiveness of theHead Space Reduction (HSR) cycle in attaining reduced and consistentdissolved oxygen (DO) levels in the finished drug product. The resultsshowed a trend with an increase in dissolved oxygen level from 0.36parts per million (ppm) recorded during compounding, to an average of5.12 ppm measured after filling, a further increase to an average of9.92 ppm while loading the Lyophilizer, and finally a reduction ofdissolved oxygen to an average of 0.50 ppm after headspace reduction.The overall trends are displayed in FIGS. 1 and 2. The plots and dataalso show that the average increase in dissolved oxygen levels fromcompounding to the filled vials was 4.76 ppm. Also, as the vials werestored in the transfer cart, an average dissolved oxygen increase ofabout 4.80 ppm was observed prior to being loaded in the Lyophilizer forhead space reduction. The total average increase in dissolved oxygenlevels from compounding to vials being loaded in the lyophilizer was9.56 ppm. The average decrease in dissolved oxygen observed in vialspost head space reduction was 9.42 ppm. In addition, the oxygen levelsobtained across all trays analyzed pre and post HSR were consistentthroughout the manufacturing process.

Head Space Gas Analysis was performed on both filled and empty vialstaken from designated locations in selected trays. Percent (%) Oxygenresults achieved across the trays showed a relatively uniform head spacereduction process throughout the chamber. The average % Oxygen for theempty vials was found to be 1.15%, compared with 1.21% for the filledvials (Reference Table 11).

Dissolved Oxygen and Head Space Gas Analysis were also performed on theHeld Vials from designated locations in Tray 1 as part of the stressedsample analysis over the course of the manufacturing process. Theresults showed a comparable trend to that observed for the regularsamples across the study (Reference Table 12). Specifically, an increasein dissolved oxygen level from 0.36 ppm recorded during compounding, to5.64 ppm measured after filling, a further increase to an average of10.58 ppm while loading the Lyophilizer, and finally a reduction ofdissolved oxygen to an average of 0.57 ppm after headspace reduction.The average % Oxygen for the filled held vials was found to be 1.48%,compared with 1.21% for the filled regular vials. This indicated thatthe HSR cycle was effective in achieving comparable DO and Headspaceoxygen results irrespective of the maximum fill time exposure(approximately 7 hours; represented by the Fill Hold Vials) and has noimpact on the quality of the product. The use of the Lyophilizer, in theHead Space Reduction of L-Cysteine Hydrochloride Injection, USP (50mg/mL) has been shown to be effective for the control of reduced andconsistent oxygen levels, and is suitable for scale up for the existingprocess and equipment as the product meets all the critical qualityattributes.

Example 5

Head space oxygen reduction was accomplished using an automated fillingequipment that can handle high speed filling, in contrast to slow or lowvolume operation such as through a lyophilizer as described in Examples1 and 4. The high-speed filler is capable of using vacuum and gasoverlay in alternate pulses to reduce the head space oxygen. Each pulseis timed to be within 0.1 to 5 seconds such that typically 3-5 pulsesare conducted in one head space oxygen reduction cycle. The pulse ratecan be adjusted after multiple trials to provide optimal headspacereduction with optimal speed of the filler such that no product is lostthrough back suction or through spillage and average speeds of fromabout 20 vials/minute to about 200 vials per minute, depending on thenumber of fill heads used.

A 50 L batch was prepared utilizing the current compounding proceduredescribed above in Example 1. The filler was set up to fill and reducehead space oxygen as per the process shown in FIG. 3.

The total head space reduction cycle lasted about 25 seconds peroperation. The vials were analyzed for head space oxygen at time zeroand at 1-month time point. The data are shown below.

The evaluation of the filler's performance demonstrated that theheadspace oxygen control was comparable to or better than the currentprocess for L-Cysteine. Headspace oxygen values obtained ranged from0.2% to 0.5% for all vials filled, including empty vials during startup. Vials tested after 1-month storage at ambient conditions alsomaintain headspace oxygen levels between 0.4 and 1.5%. The Tables belowshow a summary of the results for the in process and 1-month stabilitytesting. Also included below is a comparison of the in-process dataobtained from previously manufactured lots of L-Cysteine utilizing thelyophilizer headspace reduction method. The data show the headspaceoxygen values at Time Zero are lower with the high-speed filler than thelyophilizer process.

TABLE 14 Headspace Oxygen Levels at Time Zero for High-Speed FillerPROT-000213 - Time Zero Tray Overall Overall Tray 5 10 Low High AverageHeadspace O₂ (%) 0.473 0.378 0.243 0.490 0.372

TABLE 15 Headspace Oxygen Levels at 1 Month for High-Speed FillerPROT-000213 - 1 Month Tray No. 5 Tray No. 10 Low High Average Low HighAverage Headspace O₂ (%) 0.412 1.518 0.995 0.98 1.454 1.262

TABLE 16 Comparison of Headspace Oxygen Levels between Lyophilizer andHigh-Speed Filler Operations XMHJ1705 XMHJ1706 XMHJ1707 PROT-000213Batch (Current (Current (Current (High Speed (Process) Process) Process)Process) Filler) Average 2.3% Oxygen 1.9% Oxygen 1.9% Oxygen 0.4% OxygenLow N/A N/A N/A 0.2% Oxygen High N/A N/A N/A 0.5% Oxygen 1 Month 0.9%Oxygen 2.8% Oxygen 1.2% Oxygen 1.1% Oxygen Room (0.4% to 1.5%) Tem-perature N/A—Not Applicable

FIG. 4 shows the comparison of oxygen headspace control between thelyophilizer chamber headspace control method versus the high-speedfiller vacuum stoppering system. The lyophilizer chamber for headspacereduction was utilized for lots XMHJ1705, XMHJ1706, and XMHJ1707 ofL-Cysteine Hydrochloride injection. The time zero oxygen headspaceresults for the engineering batch PROT-000213 are shown in comparison tothe previously manufactured lots. Results shown were measured at thetime of manufacturing on samples of vials from the batches. Oxygenpercentage was taken for the samples from PROT-000213 using the NeoFoxPhase Fluorometer. Lots XMHJ1705, XMHJ1706, and XMHJ1707 used ArgonHeadspace Analysis, QCTM-000014.

In addition to the head space oxygen levels, dissolved oxygen levelswere also measured. Data are shown in FIG. 5.

The dissolved oxygen levels and head space oxygen levels were measuredagain at 1 month stability time point at room temperature conditions:

TABLE 17 Headspace and Dissolved Oxygen Data Comparison at 1 monthStudy - 1 Month Tray No. 5 Tray No. 10 Sample Sample Sample SampleSample Sample Sample 1 2 3 4 1 2 3 Head- 0.576 0.412 1.518 1.475 0.981.454 1.352 space O₂ (%) Dis- 0.545 0.706 2.328 2.042 2.173 2.372 2.149solved O₂ (ppm)

Example 6 Purity Profile and Long-Term Stability of L-CysteineComposition for Injection

An L-cysteine composition for injection was manufactured as described inExample 1. The glass used was Schott Type 1 USP Plus glass, internallycoated with silicon dioxide. The composition was subjected to stabilitytesting to evaluate the stability of the composition over time. Table 18shows various stability data collected for the L-cysteine compositionfor injection over a 9-month testing period. Samples of exhibit batchesstored upright at room temperature for 9 months at 25° C./60% RH. Note:two samples were tested for dissolved oxygen and head-space oxygen.

TABLE 18 Characterization of L-Cysteine Composition for Injection TestXMHJ1705 XMHJ1706 XMHJ1707 L-Cysteine HCl Up Up Up 100.4% 101.3% 101.2%Related Compounds: L-Cystine 0.3% 0.3% 0.3% Pyruvic Acid Total 0.1% 0.2%0.1% Specified RRT-1.98 0.2% 0.2% 0.2% Individual ND ND ND Unspecified0.5% 0.7% 0.6% Total Impurities Dissolved Oxygen (1) 0.12 ppm (1) 0.13ppm (1) 0.14 ppm (2) 0.13 ppm (2) 0.14 ppm (2) 0.13 ppm Head-SpaceOxygen (1) 0.16% (1) 0.53% (1) 0.56% (2) 0.37% (2) 0.89% (2) 0.50%Aluminum Content 3.2 ppb 2.9 ppb 5.6 ppb Description Clear colorlessClear colorless Clear colorless solution solution solution

Example 7 Effect of Dissolved Oxygen and Headspace Oxygen on L-Cysteineand Cystine Levels

An L-cysteine composition for injection was manufactured as described inExample 1. However, samples of exhibit batches were tested withouthead-space reduction and argon overlay during compounding, then filled,stoppered and capped. Samples were tested within one week ofmanufacturing date. Data in Table 19 show the marked effects of lack ofheadspace and dissolved oxygen on component levels within one week.L-Cystine increased by about 0.4%-0.7% within a week for samples withhigher dissolved oxygen and head-space oxygen.

TABLE 19 Effect of lack of Headspace and Dissolved Oxygen Control onProduct Purity Prior to Prior to Prior to Ave Values Head-SpaceHead-Space Head-Space for after Reduction Reduction Reduction completedTest Tray 1 Tray 19 Tray 23 Batch L-Cysteine HCl 99.9% 100.1% 100.0%102.0% L-Cystine 0.8% 0.5% 0.6% 0.1% Head-Space 20.8% 20.3% 20.3% 1.2%Oxygen Dissolved 8.3 ppm 8.6 ppm 8.6 ppm 0.50 ppm Oxygen

Example 8 Evaluation of Anions in L-Cysteine Product

Inorganic anionic leachables were determined using validatedpotentiometric methods utilizing ion selective electrodes. Fluoride andIodide were evaluated for this drug product. The leachables testingresults are listed in Tables 20 and 21 below.

TABLE 20 Leachable Iodide Results for L-Cysteine HCl Injection [I⁻](ppb) XMHJ1705 25° C./60% RH 40° C./75% RH Replicate Upright HorizontalInverted Upright Horizontal Inverted 1 28.1 27.4 27.1 25.2 24.9 24.7 225.9 26.3 25.9 24.0 24.1 24.1 3 28.1 25.3 25.3 24.0 22.3 21.6 Average27.4 26.3 26.1 24.4 23.7 23.5 SD 1.3 1.0 0.9 0.7 1.3 1.6 % RSD 4.7 3.93.6 2.7 5.6 7.0 XMHJ1706 25° C./60% RH 40° C./75% RH Replicate UprightHorizontal Inverted Upright Horizontal Inverted 1 81.7 80.3 82.8 80.382.0 81.8 2 83.1 81.7 81.5 82.5 82.3 81.3 3 81.7 81.7 81.8 78.1 81.982.8 Average 82.2 81.2 82.0 80.3 82.1 82.0 SD 0.8 0.8 0.7 2.2 0.2 0.7 %RSD 0.9 1.0 0.9 2.7 0.2 0.9 XMHJ1707 25° C./60% RH 40° C./75% RHReplicate Upright Horizontal Inverted Upright Horizontal Inverted 1 53.552.3 53.1 51.7 51.4 50.8 2 52.5 54.0 53.7 51.8 52.0 53.5 3 54.4 52.852.8 53.8 53.6 52.6 Average 53.5 53.0 53.2 52.4 52.3 52.3 SD 1.0 0.9 0.41.2 1.1 1.4 % RSD 1.8 1.7 0.8 2.2 2.1 2.6

TABLE 21 Leachable Iodide Results for L-Cysteine HCl Injection [I⁻](ppb) XMHL1702A XMHL1702B 25° C./ 25° C./ 60% RH 40° C./75% RH 60% RH40° C./75% RH 6 month 6 month 6 month 6 month Iodide 29 24 24 19 (ppb)The leachable results for Fluoride indicate levels below 20 ppb and noobservable trend in leachable amount over time or temperaturedependence. The leachable results for Iodide indicate that levels wereobserved ranging from ˜20-80 ppb. No noticeable trend in leachableamount including vial orientation or temperature dependence wasobserved.

Example 9 Elemental Leachables

Elemental leachables were evaluated using a validated inductivelycoupled plasma mass spectrometric (ICP-MS) method. ICP-MS method isdescribed in detail in USP and other literature in the art. The resultsfor the elemental leachables analysis are summarized in the Table below.The Table lists the Allowable Elemental Concentrations (AEC) for eachidentified element.

TABLE 22 Elemental Impurity Leachables Results for L-Cysteine HClInjection [X] (ppb) XMHJ1705 XMHJ1705 XMHJ1705 25° C/60% RH 40° C./75%RH 25° C./60% RH AEC Time point (months) Element (ppb) 1 3 6 9 1 3 6 12INV 12 HOR 12 UP Molybdenum 14537 <0.5 2 1.75 0.6 <0.5 2 0.91 0.4 0.40.5 Zinc 12598 14 2 13.84 23.4 11 38 <QL 7 5 3 Iron 12598 25 21 50.52 1916 60 5.73 9 157 637 Chromium 10660 2 <QL <QL 3.2 2 6 <QL 1 2 3 Barium6784 2 <QL <QL <QL <0.5 2 <QL 0.4 0.4 0.4 Tin 5815 1 2 3.38 1.2 3 0.88 11 1 Copper 2907 <0.5 <QL <QL 15.0 <0.5 2 <QL 0.5 0.8 0.6 Manganese 24231 <QL <QL 0.3 <0.5 2 <QL <QL 2 8 Lithium 2423 <0.5 5 3.90 0.1 <0.5 63.79 0.04 0.05 0.05 Gold 969 5 3 9.76 0.3 3 4 1.76 0.4 <QL 1 Antimony872 1 1 0.88 0.1 1 2 0.60 0.4 0.3 0.3 Selenium 775 <0.5 <QL <QL 0.1 <0.52 <QL <QL 1 <QL Nickel 194 11 9 16.66 8.1 11 9 0.99 14 14 15 Arsenic 1741 <QL <QL 0.2 1 2 <QL 0.3 0.3 0.2 Aluminum 120 <QL <QL <QL <QL <QL <QL<QL (4) (19) (5) <QL <QL <QL Vanadium 97 <QL <QL <QL <QL <0.5 4 <QL <QL<QL <QL Silver 97 <0.5 <QL <QL <QL <QL 17 <QL <QL <QL <QL Ruthenium 97<0.5 1 0.72 <QL <0.5 2 0.74 <QL <QL <QL Rhodium 97 <0.5 4 4.31 <QL <0.58 4.29 0.01 0.01 0.01 Platinum 97 <0.5 <0.5 <QL <QL <0.5 1 <QL <QL <QL<QL Palladium 97 <0.5 <QL <QL <QL <0.5 1 <QL 0.06 0.06 0.1 Osmium 97<0.5 <QL <QL <QL <0.5 1 <QL <QL <QL <QL Iridium 97 <0.5 6 5.98 <QL <0.57 5.92 0.04 0.03 0.04 Thallium 78 <0.5 4 3.59 <QL <0.5 5 3.59 <QL <QL<QL Cobalt 48 <0.5 <QL <QL 0.1 <0.5 <0.5 <QL <QL <QL <QL Lead 48 2 56.77 1.5 2 6 3.33 2 2 2 Mercury 29 <0.5 1 0.78 2 <0.5 1 1.10 0.7 0.7 0.6Cadmium 19 <0.5 1 1.31 <QL <0.5 2 1.30 <QL <QL <QL XMHJ1706 XMHJ1706XMHJ1706 25° C./60% RH 40° C./75% RH 25° C./60% RH AEC Time point(months) Element (ppb) 1 3 6 9 1 3 6 12 INV 12 HOR 12 UP Molybdenum14537 <0.5 1 1.32 0.4 <0.5 2 1.33 0.4 0.4 0.4 Zinc 12598 10 8 8.23 23.910 36 4.25 3 6 8 Iron 12598 9 30 34.02 7.9 10 41 45.60 11 55 10 Chromium10660 1 <QL <QL 1.9 2 5 <QL 1 1 1 Barium 6784 <0.5 <QL <QL <QL 1 1 <QL0.4 0.6 0.4 Tin 5815 1 2 2.91 1.3 1 3 2.08 1 2 2 Copper 2907 <QL <QL <QL<QL <QL 1 <QL 1 0.2 <QL Manganese 2423 <0.5 <QL <QL 0.3 <0.5 1 <QL 0.10.6 0.2 Lithium 2423 <0.5 4 3.84 0.1 <0.5 6 3.87 0.03 0.03 0.04 Gold 9692 3 4.38 0.2 2 4 3.99 0.2 0.2 0.3 Antimony 872 1 1 0.81 <QL 1 2 0.91 0.60.5 0.5 Selenium 775 <0.5 <QL <QL 0.6 1 3 <QL 0.4 <QL 0.4 Nickel 194 1110 8.66 8.1 11 9 8.68 14 14 14 Arsenic 174 <0.5 <QL <QL 0.4 <0.5 2 <QL0.8 0.5 0.4 Aluminum 120 <QL <QL <QL <QL <QL <QL <QL (5) (6) (1) (2) <QL<QL <QL Vanadium 97 <QL <QL <QL <QL <0.5 4 <QL <QL <QL <QL Silver 97 <QL<QL <QL <QL <QL 17 <QL <QL <QL <QL Ruthenium 97 <0.5 1 0.73 <QL <0.5 20.73 0.005 <QL 0.003 Rhodium 97 <0.5 4 4.29 <QL <0.5 8 4.28 0.007 0.0050.008 Platinum 97 <0.5 <0.5 <QL <QL <0.5 1 <QL <QL <QL <QL Palladium 97<0.5 <QL <QL <QL <0.5 1 <QL 0.04 0.02 0.03 Osmium 97 <0.5 <QL <QL <QL<0.5 1 <QL <QL <QL <QL Iridium 97 <0.5 6 5.94 <QL <0.5 7 5.94 0.03 0.030.03 Thallium 78 <0.5 4 3.59 <QL <0.5 5 3.59 <QL <QL <QL Cobalt 48 <0.5<0.5 <QL <QL <0.5 <0.5 <QL <QL <QL <QL Lead 48 2 6 5.53 2.0 2 6 5.53 2 22 Mercury 29 <0.5 1 1.11 1.5 <0.5 1 1.01 0.7 0.7 0.7 Cadmium 19 <0.5 11.30 <QL <0.5 2 1.30 <QL 0.004 <QL XMHJ1706 XMHJ1706 XMHJ1706 25° C./60%RH 40° C./75% RH 25° C./60% RH AEC Time point (months) Element (ppb) 1 36 9 1 3 6 12 INV 12 HOR 12 UP Molybdenum 14537 <0.5 1 1.22 0.4 <0.5 21.21 0.4 0.4 0.4 Zinc 12598 10 4 4.28 22.7 11 38 3.91 7 4 6 Iron 12598 826 12.55 8.3 9 74 17.68 8 71 13 Chromium 10660 1 <QL <QL 2.2 1 6 <QL 1 11 Barium 6784 <0.5 <0.5 <QL <QL <0.5 1 <QL 0.6 0.5 0.6 Tin 5815 1 2 2.133.2 1 3 2.22 1 1 1 Copper 2907 <0.5 <QL <QL <QL <0.5 2 <QL 0.2 0.2 0.1Manganese 2423 <0.5 <QL <QL 0.1 <0.5 1 <QL 0.2 1 0.3 Lithium 2423 <0.53.86 3.86 0.2 <0.5 6 3.88 0.03 0.03 0.06 Gold 969 3 3 3.98 0.1 2 4 3.480.1 0.1 0.2 Antimony 872 1 1 1.01 <QL 1 2 1.06 0.6 0.6 0.6 Selenium 775<0.5 <QL <QL 0.1 <0.5 2 <QL 0.4 <QL <QL Nickel 194 11 8 7.71 7.4 10 87.82 14 14 14 Arsenic 174 1 <QL <QL 0.4 1 2 <QL 0.6 0.6 0.6 Aluminum 120<QL <QL <QL <QL <QL <QL <QL (5) (26) (39) <QL <QL <QL Vanadium 97 <QL<QL <QL <QL <0.5 4 <QL <QL <QL <QL Silver 97 <0.5 <QL <QL <QL <QL 17 <QL<QL <QL <QL Ruthenium 97 <0.5 1 0.73 <QL <0.5 2 0.73 <QL 0.004 0.001Rhodium 97 <0.5 4 4.29 <QL <0.5 8 4.28 0.005 0.005 0.006 Platinum 97<0.5 <0.5 <QL <QL <0.5 1 <QL <QL <QL <QL Palladium 97 <0.5 <QL <QL <QL<0.5 1 <QL <QL 0.02 0.02 Osmium 97 <0.5 <QL <QL <QL <0.5 1 <QL <QL <QL<QL Iridium 97 <0.5 6 5.95 <QL <0.5 7 5.94 0.03 0.03 0.03 Thallium 78<0.5 4 3.59 <QL <0.5 5 3.56 <QL <QL <QL Cobalt 48 <0.5 <0.5 <QL <QL <0.5<0.5 <QL <QL <QL <QL Lead 48 2 6 5.51 1.9 2 6 5.55 2 2 2 Mercury 29 <0.51 0.98 1.2 <0.5 1 0.89 0.7 0.7 0.7 Cadmium 19 <0.5 1.30 1.29 <QL <0.5 21.29 <QL <QL <QL XMHJ1702A XMHJ1702A XMHJ1702A 25° C./60 % RH 25° C./60%RH 40° C./75% RH AEC Time point (months) Element (ppb) 9 INV 9 UP 0 1 23 6 0 1 2 3 6 Molybdenum 14537 1 0.5 2 N/A N/A 1.34 0.5 2 2 <0.5 1 0.4Zinc 12598 17 17 42 N/A N/A 3.90 34.3 42 37 2 4 22.1 Iron 12598 5 59 284N/A N/A 15.31 7 284 27 <QL 35 11.2 Chromium 10660 5 1 14 N/A N/A <QL 2.114 4 <0.5 <QL 2.1 Barium 6784 1 0.4 2 N/A N/A <QL <QL 2 2 <QL <QL <QLTin 5815 2 1 3 N/A N/A 1.82 3.8 3 3 2 2 1 Copper 2907 1 0.4 4 N/A N/A<QL 123.1 4 2 <QL <QL 0.1 Manganese 2423 2 1 5 N/A N/A <QL 0.1 5 1 <0.5<QL 0.3 Lithium 2423 8 0.1 6 N/A N/A 3.92 0.2 6 6 <QL 4 0.2 Gold 969 7 17 N/A N/A 3.45 0.1 7 4 5 4 0.1 Antimony 872 <QL 0.3 2 N/A N/A 1.08 <QL 22 1 1 <QL Selenium 775 <QL <QL 4 N/A N/A <QL 0.4 4 2 <QL <QL <QL Nickel194 11 15 11 N/A N/A 8.93 8 11 9 4 8 8.1 Arsenic 174 0.3 0.1 2 N/A N/A<QL 0.3 2 1 <QL <QL 0.3 Aluminum 120 (9) (5) <0.5 N/A N/A <QL <QL <QL(3) (8) (7) <QL <QL <QL <QL <QL <QL Vanadium 97 3 <QL 4 N/A N/A <QL <QL4 3 <QL <QL <QL Silver 97 2 <QL 17 N/A N/A <QL <QL 17 17 17 <QL <QLRuthenium 97 0.9 <QL 2 N/A N/A 0.76 <QL 2 2 <0.5 1 <QL Rhodium 97 8 0.018 N/A N/A 4.30 <QL 8 8 9 4 <QL Platinum 97 2 <QL 1 N/A N/A <QL 0.1 1 1<0.5 <0.5 0.1 Palladium 97 1 0.1 1 N/A N/A <QL <QL 1 1 <QL <QL <QLOsmium 97 0.8 <QL 1 N/A N/A <QL <QL 1 1 1 <QL <QL Iridium 97 10 0.04 7N/A N/A 5.98 <QL 7 7 9 6 <QL Thallium 78 7 <QL 5 N/A N/A 3.59 <QL 5 5 64 <QL Cobalt 48 3 0.03 <0.5 N/A N/A <QL <QL <0.5 <0.5 <QL <0.5 <QL Lead48 8 2 6 N/A N/A 5.01 1.6 6 6 6 5 1.5 Mercury 29 1 0.6 2 N/A N/A 0.81 12 1 1 1 1.1 Cadmium 19 0.5 <QL 2 N/A N/A 1.37 <QL 2 2 1 1 <QL XMHJ1702BXMHJ1702B 25° C./60% RH 40° C./75% RH AEC Time point (months) Element(ppb) 0 1 2 3 6 0 1 2 3 6 Molybdenum 14537 2 N/A N/A 1 0.5 2 2 <QL 1 0.4Zinc 12598 38 N/A N/A 71 23.5 38 39 <QL 7 23.1 Iron 12598 166 N/A N/A 317.9 166 35 <QL 16 12.3 Chromium 10660 9 N/A N/A <QL 2.1 9 6 <QL <QL 1.9Barium 6784 1 N/A N/A <QL <QL 1 1 <QL <QL <QL Tin 5815 3 N/A N/A 21 1.53 4 3 3 1.3 Copper 2907 2 N/A N/A <QL <QL 2 2 <QL <QL 0.3 Manganese 24233 N/A N/A <QL 0.1 3 1 <QL <QL 0.3 Lithium 2423 6 N/A N/A 4 0.2 6 6 <QL 40.2 Gold 969 5 N/A N/A 3 0.1 5 4 5 3 0.1 Antimony 872 2 N/A N/A 1 <QL 22 1 1 <QL Selenium 775 3 N/A N/A <QL 0.1 3 2 <QL <QL <QL Nickel 194 10N/A N/A 9 8.2 10 8 4 8 8.2 Arsenic 174 2 N/A N/A <QL 0.3 2 2 <QL <QL 0.1Aluminum 120 <QL N/A N/A (6) <QL <QL (10) (25) (6) <QL <QL <QL <QL <QLVanadium 97 4 N/A N/A <QL <QL 4 4 <QL <QL <QL Silver 97 17 N/A N/A <QL<QL 17 17 17 <QL <QL Ruthenium 97 2 N/A N/A 1 <QL 2 2 <0.5 1 <QL Rhodium97 8 N/A N/A 4 <QL 8 8 9 4 <QL Platinum 97 1 N/A N/A <0.5 0.1 1 1 <0.5<0.5 0.1 Palladium 97 1 N/A N/A <QL <QL 1 1 <QL <QL <QL Osmium 97 1 N/AN/A <QL <QL 1 1 1 <QL <QL Iridium 97 7 N/A N/A 6 <QL 7 7 9 6 <QLThallium 78 5 N/A N/A 4 <QL 5 5 6 4 <QL Cobalt 48 <0.5 N/A N/A <0.5 <QL<0.5 <0.5 <QL <0.5 <QL Lead 48 6 N/A N/A 5 1.5 6 6 6 5 1.5 Mercury 29 2N/A N/A 1 0.5 2 1 1 1 0.4 Cadmium 19 2 N/A N/A 1 <QL 2 2 1 1 <QL

Example 10 Visual Inspection of Filled Vials

The L-Cysteine product that was manufactured by the two methods (i.e.,lyophilzer chamber method and high-speed filler method) were inspectedat after 1 month after production for visible signs of degradation inthe form of visible particulate matter. In the presence of oxygen, twoL-Cysteine residues will form a disulfide covalent bond formingL-Cystine. L-Cystine has a lower solubility (0.112 mg/mL) thanL-Cysteine (50 mg/mL), in some cases the degradant can be visuallyobserved.

TABLE 23 Comparison of Particulate Matter PROT-000213 XMHJ1705 XMHJ1706XMHJ1707 Total Vials 1918 3473 3473 3497 White PM 36 120 31 32 Overall %1.88% 3.46% 0.89% 0.92%

As the data show, no confirmed degradation was observed by either methodindicating that the head space oxygen reduction and dissolved oxygenlevels achieved herein are successful in producing L-Cysteine injectionof desirable quality attributes.

All documents cited or referenced in the application cited documents,and all documents cited or referenced herein (“herein cited documents”),and all documents cited or referenced in herein cited documents,together with any manufacturer's instructions, descriptions, productspecifications, and product sheets for any products mentioned herein orin any document incorporated by reference herein, are herebyincorporated herein by reference, and may be employed in the practice ofthe invention.

As used herein, “a,” “an,” or “the” can mean one or more than one. Forexample, “a” cell can mean a single cell or a multiplicity of cells.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

The term “consists essentially of” (and grammatical variants), asapplied to the compositions of this invention, means the composition cancontain additional components as long as the additional components donot materially alter the composition.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. Unless otherwise stated,use of the term “about” in accordance with a specific number ornumerical range should also be understood to provide support for suchnumerical terms or range without the term “about”. For example, for thesake of convenience and brevity, a numerical range of “about 50milligrams to about 80 milligrams” should also be understood to providesupport for the range of “50 milligrams to 80 milligrams.” Furthermore,it is to be understood that in this written description support foractual numerical values is provided even when the term “about” is usedtherewith. Furthermore, the term “about,” as used herein when referringto a measurable value such as an amount of a compound or agent of thisinvention, dose, time, temperature, and the like, is meant to encompassvariations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of thespecified amount. To be clear, the range encompassed by “about” willinclude all discrete values within that range, regardless of whethersuch discrete values are explicitly specified and/or prefaced by“about.” Equivalents permissible for such discrete values as well as allranges and subranges are within the scope of this disclosure.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. Thissame principle applies to ranges reciting only one numerical value as aminimum or a maximum. Furthermore, such an interpretation should applyregardless of the breadth of the range or the characteristics beingdescribed.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. A method of treating a subject having an adversehealth condition that is responsive to L-cysteine administration, saidmethod comprising: parenterally administering to said subject aparenteral composition comprising a mixture of one or more amino acids,intravenous fluid, and a stable L-cysteine composition, wherein saidstable L-cysteine composition contributes to said parenteralcomposition: a therapeutically effective amount of L-cysteine or apharmaceutically acceptable salt thereof and/or hydrate thereof; perLiter of said stable L-cysteine composition, from about 1.0 mcg to about250 mcg of Aluminum; not more than about 2.0 wt % of cystine relative toL-cysteine; and, not more than about 2.0 wt % of pyruvic acid relativeto L-cysteine.
 2. The method of claim 1, wherein said stable L-cysteinecomposition contributes Aluminum in an amount less than 200 mcg/L. 3.The method of claim 1, wherein said stable L-cysteine compositioncontributes Aluminum in an amount less than 150 mcg/L.
 4. The method ofclaim 1, wherein said parenteral composition is a total parenteralnutrition (TPN) composition.
 5. The method of claim 1, wherein saidintravenous fluid is selected from the group consisting of isotonicsaline, glucose solution, glucose saline, dextrose solution, crystallineamino acid solution, and lipids, and combinations thereof.
 6. The methodof claim 1, wherein said intravenous fluid is selected from the groupconsisting of isotonic saline, dextrose solution, and crystalline aminoacid solution, and combinations thereof.
 7. The method of claim 1,wherein said parenteral composition further comprises one or more aminoacids selected from the group consisting of leucine, isoleucine, lysine,valine, phenylalanine, histidine, threonine, methionine, tryptophan,alanine, arginine, glycine, proline, serine, and tyrosine.
 8. The methodof claim 1, wherein said administering comprises administration once ortwice daily.
 9. The method of claim 8, wherein said parenterallyadministering delivers about 120 mg/kg/day to about 160 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 10. The method of claim 8, wherein said parenterallyadministering delivers about 80 mg/kg/day to about 120 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 11. The method of claim 8, wherein said parenterallyadministering delivers about 40 mg/kg/day to about 80 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 12. The method of claim 8, wherein said parenterallyadministering delivers about 45 mg/kg/day to about 60 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 13. The method of claim 8, wherein said parenterallyadministering delivers about 30 mg/kg/day to about 45 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 14. The method of claim 8, wherein said parenterallyadministering delivers about 15 mg/kg/day to about 30 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 15. The method of claim 8, wherein said parenterallyadministering delivers about 7 mg/kg/day to about 10 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 16. The method of claim 8, wherein said parenterallyadministering delivers about 4 mg/kg/day to about 7.5 mg/kg/dayL-cysteine, or a pharmaceutically acceptable salt thereof and/or hydratethereof.
 17. The method of claim 1, wherein said subject is a preterminfant or less than about 1 month of age.
 18. The method of claim 1,wherein said subject has an age of 1 month to 1 year.
 19. The method ofclaim 1, wherein said subject has an age of 1 year to 11 years.
 20. Themethod of claim 1, wherein said subject has an age of 12 years to 17years.
 21. The method of claim 1, wherein said subject is an adult. 22.The method of claim 17, wherein said administering delivers about 15 mgof said L-cysteine per gram of said one or more amino acids, and saidL-cysteine composition contributes not more than 0.21 mcg/kg/day ofAluminum.
 23. The method of claim 1, wherein said adverse healthcondition results from the inability to convert methionine toL-cysteine.
 24. The method of claim 1, wherein said adverse healthcondition is the need for total parenteral nutrition (TPN).
 25. Themethod of claim 1, wherein said adverse health condition is selectedfrom the group consisting of short bowel syndrome, gastrointestinalfistula, bowel obstruction, prolonged bowel rest, severe malnutrition,significant weight loss and/or hypoproteinaemia, and a condition thatprecludes oral or enteral feeding.
 26. The method of claim 1, whereinsaid adverse health condition is selected from the group consisting ofthe need for total parenteral nutrition (TPN), osteoarthritis,rheumatoid arthritis, angina, chronic bronchitis, chronic obstructivepulmonary disease (COPD), influenza, acute respiratory distress syndrome(ARDS), and diabetes.
 27. A method of treating a subject having anadverse health condition that is responsive to L-cysteineadministration, said method comprising: parenterally administering tosaid subject a parenteral composition comprising a mixture comprising astable L-cysteine composition, wherein said stable L-cysteinecomposition contributes to said parenteral composition: atherapeutically effective amount of L-cysteine or a pharmaceuticallyacceptable salt thereof and/or hydrate thereof; per Liter of said stableL-cysteine composition, not more than 150 mcg of Aluminum; cystinerelative to L-cysteine not more than about 2.0 wt %; and, pyruvic acidrelative to L-cysteine not more than about 2.0 wt %.
 28. A totalparenteral nutritional composition comprising a mixture of: a stableL-cysteine composition, wherein said stable L-cysteine compositioncontributes to said total parenteral nutritional composition: L-cysteineor a pharmaceutically acceptable salt thereof and/or hydrate thereof;per Liter of said stable L-cysteine composition, from about 10 mcg toabout 250 mcg of Aluminum; cystine in an amount from about 0.001 wt % toabout 2.0 wt % relative to L-cysteine; pyruvic acid in an amount fromabout 0.001 wt % to about 2.0 wt % relative to L-cysteine; one or moreamino acids selected from the group consisting of: leucine, isoleucine,lysine, valine, phenylalanine, histidine, threonine, methionine,tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine;and, a pharmaceutically acceptable carrier, comprising water.
 29. Thetotal parenteral nutritional composition of claim 28, wherein the amountof L-Cysteine is from about 15 mg to about 40 mg per gram of said aminoacids.
 30. The total parenteral nutritional composition of claim 28,comprising said L-Cysteine from about 20 mg/mL to about 80 mg/mL of saidparenteral nutritional composition.